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1
Dimitroulakos, Jim, Dana Nohynek, Karen L. Backway, David W. Hedley, Herman Yeger, Melvin H. Freedman, Mark D. Minden, and Linda Z. Penn. "Increased Sensitivity of Acute Myeloid Leukemias to Lovastatin-Induced Apoptosis: A Potential Therapeutic Approach." Blood 93, no. 4 (February 15, 1999): 1308–18. http://dx.doi.org/10.1182/blood.v93.4.1308.
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Abstract We recently demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of de novo cholesterol synthesis, was a potential mediator of the biological effects of retinoic acid on human neuroblastoma cells. The HMG-CoA reductase inhibitor, lovastatin, which is used extensively in the treatment of hypercholesterolemia, induced a potent apoptotic response in human neuroblastoma cells. This apoptotic response was triggered at lower concentrations and occurred more rapidly than had been previously reported in other tumor-derived cell lines, including breast and prostate carcinomas. Because of the increased sensitivity of neuroblastoma cells to lovastatin-induced apoptosis, we examined the effect of this agent on a variety of tumor cells, including leukemic cell lines and primary patient samples. Based on a variety of cytotoxicity and apoptosis assays, the 6 acute lymphocytic leukemia cell lines tested displayed a weak apoptotic response to lovastatin. In contrast, the majority of the acute myeloid leukemic cell lines (6/7) and primary cell cultures (13/22) showed significant sensitivity to lovastatin-induced apoptosis, similar to the neuroblastoma cell response. Of significance, in the acute myeloid leukemia, but not the acute lymphocytic leukemia cell lines, lovastatin-induced cytotoxicity was pronounced even at the physiological relevant concentrations of this agent. Therefore, our study suggests the evaluation of HMG-CoA reductase inhibitors as a therapeutic approach in the treatment of acute myeloid leukemia.
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Dimitroulakos, Jim, Dana Nohynek, Karen L. Backway, David W. Hedley, Herman Yeger, Melvin H. Freedman, Mark D. Minden, and Linda Z. Penn. "Increased Sensitivity of Acute Myeloid Leukemias to Lovastatin-Induced Apoptosis: A Potential Therapeutic Approach." Blood 93, no. 4 (February 15, 1999): 1308–18. http://dx.doi.org/10.1182/blood.v93.4.1308.404k08_1308_1318.
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We recently demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of de novo cholesterol synthesis, was a potential mediator of the biological effects of retinoic acid on human neuroblastoma cells. The HMG-CoA reductase inhibitor, lovastatin, which is used extensively in the treatment of hypercholesterolemia, induced a potent apoptotic response in human neuroblastoma cells. This apoptotic response was triggered at lower concentrations and occurred more rapidly than had been previously reported in other tumor-derived cell lines, including breast and prostate carcinomas. Because of the increased sensitivity of neuroblastoma cells to lovastatin-induced apoptosis, we examined the effect of this agent on a variety of tumor cells, including leukemic cell lines and primary patient samples. Based on a variety of cytotoxicity and apoptosis assays, the 6 acute lymphocytic leukemia cell lines tested displayed a weak apoptotic response to lovastatin. In contrast, the majority of the acute myeloid leukemic cell lines (6/7) and primary cell cultures (13/22) showed significant sensitivity to lovastatin-induced apoptosis, similar to the neuroblastoma cell response. Of significance, in the acute myeloid leukemia, but not the acute lymphocytic leukemia cell lines, lovastatin-induced cytotoxicity was pronounced even at the physiological relevant concentrations of this agent. Therefore, our study suggests the evaluation of HMG-CoA reductase inhibitors as a therapeutic approach in the treatment of acute myeloid leukemia.
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Xiong, Jie, Xingyi Kuang, Tingting Lu, Bingqing Cheng, Danna Wei, Xinyao Li, Weili Wang, Zhaoyuan Zhang, and Jishi Wang. "The Crucial Role of NR4A1 Dependent Apoptosis Induced By Fenretinide in Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 5266. http://dx.doi.org/10.1182/blood-2018-99-117776.
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Abstract OBJECTIVE: NR4A1 is a member of the orphan nuclear receptor family, which is involved in biological processes such as cell proliferation, apoptosis, metabolism, and differentiation. The expression of NR4A1 is increased in a variety of solid tumors, which promotes oncogenesis and enhances the viability of tumor cells. However, in hematological malignancies, its expression is significantly lower than normal. Studies have shown that clearance of NR4A1 can lead to the progression of mice to acute myeloid leukemia, reducing the amount of NR4A gene expression can make mice progress to MDS / MPN, and even acute myeloid leukemia. This indicates that NR4A1 is an important tumor suppressor in acute myeloid leukemia. The present study was to investigate the effect of drug-induced NR4A1 expression on apoptosis in acute myeloid leukemia and its related mechanisms. The results suggested that NR4A1 may become a new target for the treatment of acute myeloid leukemia. METHODS: In vitro, on the one hand, bone marrow mononuclear cells from patients with newly diagnosed or relapsed acute myeloid leukemia were extracted as samples, and the expression of NR4A1 mRNA and protein was detected by Real-time PCR and Western blot. Acute myeloid leukemia cell lines HL60 and Kasumi-1 were tested for fenretinide activity and apoptosis, as well as NR4A1 and mitochondrial apoptosis pathway-related protein expression. We used siNR4A1 to knockdown NR4A1 expression and LMB to inhibit nuclear export, the apoptosis rate and apoptosis protein were detected. The mechanism of anti-apoptotic effect of NR4A1 was verified by western blot, immunofluorescence and co-immunoprecipitation. AML mice model were established and fenretinide was injected into the tail veins to observe the effects of NR4A1 expression on survival time, blood routine, bone marrow and important organs. Results: 1. NR4A1 expression in patients with acute myeloid leukemia was significantly higher than normal. 2. The expression of NR4A1 increased in a time- and concentration-dependent manner under the action of fenretinide. 3. After siNR4A1, the apoptosis of acute myeloid leukemia cells was significantly decreased, and the expression of apoptotic proteins was decreased. 4. The expression of apoptotic proteins was decreased after fenretinide combined with leptomycin treatment. After fenretinide treatment, the expression of NR4A1 was decreased in nuclear extracts, and the expression of mitochondrial extract was increased. After drug treatment, NR4A1 interacted with Bcl-2, and the bcl-2 BH3 domain in cytoplasm was exposed to play an anti-apoptotic effect. After successful modeling of AML mice, the survival rate of the fenretinide treatment group was significantly prolonged compared with the control group. The peripheral blood leukocytes, hemoglobin and platelet values were significantly different. The liver and spleen volume of the treatment group were significantly smaller than that of the control group. The mRNA and protein levels of NR4A1 in the spleen were significantly higher than those in the control group. Conclusion: The effect of fenretinide on acute myeloid leukemia cells induces NR4A1 expression and plays a pro-apoptotic effect. This apoptosis effect depends on the nuclear export of NR4A1. NR4A1 is located from the nucleus to the mitochondria, and binds to the Bcl-2 BH3 domain. Key words: NR4A1, fenretinide, acute myeloid leukemia, apoptosis, nuclear export Disclosures No relevant conflicts of interest to declare.
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Testa, U., and R. Riccioni. "Deregulation of apoptosis in acute myeloid leukemia." Haematologica 92, no. 1 (January 1, 2007): 81–94. http://dx.doi.org/10.3324/haematol.10279.
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Del Principe, Maria Ilaria, Giovanni Del Poeta, Adriano Venditti, Francesco Buccisano, Luca Maurillo, Carla Mazzone, Antonio Bruno, et al. "Apoptosis and immaturity in acute myeloid leukemia." Hematology 10, no. 1 (February 2005): 25–34. http://dx.doi.org/10.1080/10245330400020454.
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Strati, Paolo, Courtney DiNardo, Naval Daver, Michael Andreeff, and Marina Konopleva. "Targeting Apoptosis Pathways in Acute Myeloid Leukemia." Clinical Lymphoma Myeloma and Leukemia 19 (September 2019): S53—S54. http://dx.doi.org/10.1016/j.clml.2019.07.417.
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de Melo Silva, Alex José. "Bcl-2 Family Overexpression and Chemoresistance in Acute Myeloid Leukemia." Serbian Journal of Experimental and Clinical Research 19, no. 4 (December 1, 2018): 299–309. http://dx.doi.org/10.2478/sjecr-2018-0064.
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Abstract The family of Bcl-2 proteins is one of the most responsible for apoptosis pathway, that is a critical process to the maintenance of tissue homeostasis. Bcl-2 is an essential apoptotic regulator belonging to a family of functionally and structurally related proteins known as the Bcl-2 family. Some members of this family act as anti-apoptotic regulators, whereas others act in pro-apoptotic function. The relationship between the pro and anti-apoptotic proteins can regulate whether cells begin the apoptosis or remain its life cycle. Increasing of Bcl-2 expression has been found in some hematologic diseases, such as Acute Myeloid Leukemia (AML) and their effects on responsiveness to anticancer therapy have been recently described. Thus, this review aims to discuss apoptosis and the role of the Bcl-2 family of proteins in chemoresistance when overexpressed in patients committed with Acute Myeloid Leukemia submitted to chemotherapy treatment.
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Shah, Mithun Vinod, Karen S. Flatten, B. Douglas Smith, Allan D. Hess, and Scott H. Kaufmann. "MTH1 Inhibitor-Induced Cytotoxicity in Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 1273. http://dx.doi.org/10.1182/blood.v126.23.1273.1273.
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Abstract BACKGROUND: Acute myeloid leukemia (AML) is an aggressive leukemia with 5-year overall survival of 20-25%. The major reason for treatment failure in AML is resistance to chemotherapy. Thus, there is an urgent need for identification of novel therapeutic agents for AML. Neoplastic cells, including AML, have dysfunctional redox regulation that results in increased reactive oxygen species (ROS). Accumulation of ROS leads to oxidation of free and incorporated nucleotides, leading to DNA damage and cell death. MTH1 is a nudix family hydrolase that sanitizes the oxidized nucleotide pool to prevent incorporation of these damaged bases in the DNA. MTH1 is thought to be non-essential for normal cells but crucial for neoplastic cells in order to avoid incorporation of oxidized dNTPs into DNA, thereby evading DNA damage and cell death. Whether MTH1 inhibitors have any activity against AML is not known. METHODS: Neoplastic myeloid cell lines HL-60, HEL, K562, KG1A, ML1, MV-4-11, SET2, and U937 were treated with varying concentrations of TH588 for a total of 48 hours. In experiments using the pan-caspase inhibitor Q-VD-OPh (Qvd), cells were pre-treated with 5µM Qvd for 1 hour followed by TH588. Cells were washed and stained with annexin, propidium iodide (PI), or MitoTracker (Life Technologies, Carlsbad, CA) for flow cytometry. To evaluate the potential impact of MTH1 inhibition on chemorefractory AML, HL-60/VCR cells were treated with vehicle control or TH588 in culture medium with or without vincristine (1µg/ml). Percentage apoptosis was calculated by normalizing to vehicle only control. With IRB approval, bone marrow aspirate samples were obtained from patients with untreated AML or healthy controls. Mononuclear cells were analyzed using colony-forming unit (CFU) assays. The total number of erythroid (CFU-E) and myeloid (CFU-G, CFU-GM) colonies containing ≥50 cells were read on day 14 and reported as percentage colonies compared to vehicle control. RESULTS: TH588 induced dose-dependent cell death in each of the neoplastic cell lines tested except HEL. In particular, treatment with TH588 resulted in a dose-dependent increase in the number of cells undergoing apoptosis as indicated by annexin V and/or PI staining (IC50 3.1-21.3µM, Figure 1). Pre-treatment with Qvd significantly inhibited TH588-induced cell death in all the cell lines studied except KG1A and SET2, suggesting a caspase-dependent mechanism of cell death. In further studies, cells treated with TH588 exhibited decreased MitoTracker staining; and Qvd pretreatment increased the number of MitoTrackerLow cells at the same time apoptotic cells decreased, suggesting that mitochondrial damage is upstream of caspase activation in TH588-induced apoptosis. Treatment with TH588 not only induced apoptosis in HL-60/VCR cells, but also facilitated further apoptosis in cells co-treated with vincristine and TH588 (Figure 2). Treatment with TH588 also diminished colony formation in a primary AML sample (IC50 6µM, Figure 3). Analysis of additional primary AML samples is ongoing. DISCUSSION: Our results show that the MTH1 inhibitor TH588 induces apoptosis in most neoplastic myeloid cells. MTH1 causes mitochondrial damage that, in turn, leads to caspase-dependent apoptosis in these cells. In HL-60/VCR cells representing chemorefractory phenotype, TH588 induces apoptosis as a single agent and resensitizes cells to vincristine. Moreover, TH588 significantly diminished colony formation in primary AML ex vivo. Further preclinical and possible clinical study of this class of agent appears warranted. Figure 1. Induction of cell death by MTH1 inhibitor TH588 in neoplastic myeloid cell lines. Figure 1. Induction of cell death by MTH1 inhibitor TH588 in neoplastic myeloid cell lines. Figure 2. TH588 induces apoptosis in HL-60/VCR cells and resensitizes cells to vincristine. Figure 2. TH588 induces apoptosis in HL-60/VCR cells and resensitizes cells to vincristine. Figure 3. TH588 significantly diminished colony formation in primary AML ex vivo indose-dependent manner. Figure 3. TH588 significantly diminished colony formation in primary AML ex vivo indose-dependent manner. Disclosures No relevant conflicts of interest to declare.
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Garzon, Ramiro, Catherine E. A. Heaphy, Violaine Havelange, Muller Fabbri, Stefano Volinia, Twee Tsao, Nicola Zanesi, et al. "MicroRNA 29b functions in acute myeloid leukemia." Blood 114, no. 26 (December 17, 2009): 5331–41. http://dx.doi.org/10.1182/blood-2009-03-211938.
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Abstract MicroRNAs (miRNAs) are associated with cytogenetics and molecular subtypes of acute myelogeneous leukemia (AML), but their impact on AML pathogenesis is poorly understood. We have previously shown that miR-29b expression is deregulated in primary AML blasts. In this work, we investigated the functional role of miR-29b in leukemogenesis. Restoration of miR-29b in AML cell lines and primary samples induces apoptosis and dramatically reduces tumorigenicity in a xenograft leukemia model. Transcriptome analysis after ectopic transfection of synthetic miR-29b into leukemia cells indicates that miR-29b target apoptosis, cell cycle, and proliferation pathways. A significant enrichment for apoptosis genes, including MCL-1, was found among the mRNAs inversely correlated with miR-29b expression in 45 primary AML samples. Together, the data support a tumor suppressor role for miR-29 and provide a rationale for the use of synthetic miR-29b oligonucleotides as a novel strategy to improve treatment response in AML.
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Roma, Alessia, Sarah G. Rota, and Paul A. Spagnuolo. "Diosmetin Induces Apoptosis of Acute Myeloid Leukemia Cells." Molecular Pharmaceutics 15, no. 3 (February 7, 2018): 1353–60. http://dx.doi.org/10.1021/acs.molpharmaceut.7b01151.
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Rosso, Valentina, Cristina Panuzzo, Jessica Petiti, Sonia Carturan, Matteo Dragani, Giacomo Andreani, Carmen Fava, Giuseppe Saglio, Enrico Bracco, and Daniela Cilloni. "Reduced Expression of Sprouty1 Contributes to the Aberrant Proliferation and Impaired Apoptosis of Acute Myeloid Leukemia Cells." Journal of Clinical Medicine 8, no. 7 (July 4, 2019): 972. http://dx.doi.org/10.3390/jcm8070972.
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In most of the acute myeloid leukemia patients there is an aberrant tyrosine kinase activity. The prototype of Sprouty proteins was originally identified in Drosophila melanogaster as antagonists of Breathless, the mammalian ortholog of fibroblast growth factor receptor. Usually, SPRY family members are inhibitors of RAS signaling induced by tyrosine kinases receptors and they are implicated in negative feedback processes regulating several intracellular pathways. The present study aims to investigate the role of a member of the Sprouty family, Sprouty1, as a regulator of cell proliferation and growth in patients affected by acute myeloid leukemia. Sprouty1 mRNA and protein were both significantly down-regulated in acute myeloid leukemia cells compared to the normal counterpart, but they were restored when remission is achieved after chemotherapy. Ectopic expression of Sprouty1 revealed that it plays a key role in the proliferation and apoptotic defect that represent a landmark of the leukemic cells. Our study identified Sprouty1 as negative regulator involved in the aberrant signals of adult acute myeloid leukemia. Furthermore, we found a correlation between Sprouty1 and FoxO3a delocalization in acute myeloid leukemia (AML) patients at diagnosis, suggesting a multistep regulation of RAS signaling in human cancers.
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Valentin, Rebecca, Stephanie Grabow, and Matthew S. Davids. "The rise of apoptosis: targeting apoptosis in hematologic malignancies." Blood 132, no. 12 (September 20, 2018): 1248–64. http://dx.doi.org/10.1182/blood-2018-02-791350.
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Abstract Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family consists of regulatory proteins that either induce apoptosis (proapoptotic) or inhibit it (prosurvival). BCL-2, myeloid cell leukemia-1, and B-cell lymphoma–extra large are prosurvival proteins that are prime targets for anticancer therapy, and molecules targeting each are in various stages of preclinical and clinical development. The US Food and Drug Administration (FDA)-approved BCL-2 inhibitor venetoclax was first proven to be highly effective in chronic lymphocytic leukemia and some B-cell non-Hodgkin lymphoma subtypes. Subsequently, venetoclax was found to be active clinically against a diverse array of hematologic malignancies including multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, and others. Here, we give a brief introduction to BCL-2 family biology and the mechanism of action of BCL-2 Homology 3 (BH3) mimetics, and provide an overview of the clinical data for therapeutically targeting prosurvival proteins in hematologic malignancies, with a focus on BCL-2 inhibition. To prioritize novel agent combinations and predict responders, we discuss the utility of functional assays such as BH3 profiling. Finally, we provide a perspective on how therapies targeting BCL-2 family proteins may be optimally implemented into future therapeutic regimens for hematologic malignancies.
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Yuk, Yen Ju, Young Jin Seo, Hyoung Jin Kang, Mi Kyoung Jang, Ji Won Lee, Hye Ry Kim, Eun Jong Han, Hee Young Shin, and Hyo Seop Ahn. "Hypoxia Suppresses Arsenic Trioxide-Induced Apoptosis in Human Acute Myeloid Leukemia Cells." Blood 114, no. 22 (November 20, 2009): 3109. http://dx.doi.org/10.1182/blood.v114.22.3109.3109.
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Abstract Abstract 3109 Poster Board III-46 Acute myeloid leukemia (AML) is a class of prevalent hematopoietic malignancies, which often remains incurable because of the development of drug resistance. Leukemic cells originated from hypoxic condition in bone marrow that gives a benefit to leukemic cells by protecting them from anti-cancer drugs through physical barrier and by induction of some survival signal mediators. As the development of drug resistance is a key element in the failure of chemotherapy for leukemia, it has been studied about many factors make leukemic cells resist to chemotherapeutic drugs. However, effect of hypoxia on drug induced apoptosis is still poorly understood. Here, we investigated whether hypoxia affects the resistance to drugs in leukemic cells and whether hypoxia has some role in drug-induced apoptosis. To demonstrate whether hypoxia influences the apoptosis of human leukemic cells induced by chemotherapeutic drugs, the human AML cell lines (U937, HL-60, CCRF-CEM and K562) were treated with arsenic trioxide (ATO), actinomycin-D, 17-AAG, valproic acid and cytrabine under hypoxic condition and hypoxiamimetic agent cobalt chloride (CoCl2). Cellular proliferation was evaluated by methyl thiazolyl tetrazolium (MTT) assay. Subsequently, FACS analysis and western blot were performed to investigate the apoptosis related proteins. Among AML cell lines, HL-60 cells became resistant to apoptosis induced by chemotherapeutic drug, especially ATO, under the hypoxic condition. It was demonstrated through FACS analysis that level of Annexin-V staining in hypoxia (13.58%) was lower than in normoxia (29.07%). Also, among many apoptosis related molecules, activation of HIF-1 alpha under hypoxic condition was associated with the cell survival (HSP70) and apoptosis (BAX). Expression of HSP70 was increased and the level of BAX was dramatically down-regulated by HSP70 in ATO treated HL-60 cells. These data show that the hypoxia increases resistance to ATO induced apoptosis and the effect was mediated by HSP70/BAX dependent pathway. Collectively, this results provided several lines of direct evidence for the role of hypoxia on apoptosis of AML cells, in which HSP 70 and BAX elicit a role as an effector downstream to HIF-1alpha. These discoveries would shed new insights for understanding underlying mechanisms of hypoxia and designing new therapeutic strategy for AML. Disclosures No relevant conflicts of interest to declare.
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Mazar, Julia, Alexandra Lichtenstein, Leora Katz, Ofer Shpilberg, Itai Levi, and Ilana Nathan. "TPCK Induces Apoptosis in Human Acute Myeloid Leukemia U-937 Cells." Blood 104, no. 11 (November 16, 2004): 4478. http://dx.doi.org/10.1182/blood.v104.11.4478.4478.
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Abstract Many types of antitumor therapy in general and AML in particular exert their effect by activating apoptosis. Apoptosis of AML cells can be induced by cytostatic drugs, corticosteroids, and radiation. Recently, the role of different proteases as possible targets for chemotherapy was described. N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a chymotrypsin-like protease (CLP) inhibitor was shown to exert a dual effect on leukemic cells: proapoptotic and antiapoptotic. In the present study the mechanism of its proapoptotic effect was addressed. It was found that the CLP inhibitors, TPCK and 3,4 dichloroisicoumarine induced apoptosis in a time- and concentration-dependent manner. Apoptosis was accompanied by a decrease in mitochondrial membrane potential, cytochrome c release, caspase-3 (but not caspase-8) activation, PS flip-flop (measured by Annexin-V staining followed by flow cytometry analysis) and chromatin condensation, but not fragmentation (detected by acridine orange/ethidium bromide staining). All apoptotic processes induced by TPCK were completely inhibited by cycloheximide. The ability of cycloheximide to inhibit TPCK-induced cell death suggests that protein synthesis plays a role in TPCK-induced apoptosis. Additionaly, the proapoptotic effect of TPCK was abolished by elimination of glucose from the medium. The data supports the role of mitochondria in this process. In the present study the apoptotic pathway driven by inhibition of CLP was demonstrated. Moreover, these findings suggest possible ways of preventing the proapoptotic activity of TPCK and thereby enhancimg its antiapoptotic action.
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Pan, Pan, and Xiao Chen. "Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia." Cells 9, no. 9 (August 19, 2020): 1921. http://dx.doi.org/10.3390/cells9091921.
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The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating the differentiation of myeloid cells, making them attractive therapeutic targets for myeloid leukemia. To date, the success of all-trans retinoic acid (ATRA) in treating acute promyelocytic leukemia (APL) remains a classical and unsurpassable example of cancer differentiation therapy. ATRA targets retinoic acid receptor (RAR) and forces differentiation and/or apoptosis of leukemic cells. In addition, ligands/agonists of vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) have also been shown to inhibit proliferation, induce differentiation, and promote apoptosis of leukemic cells. Encouragingly, combining different NR agonists or the addition of NR agonists to chemotherapies have shown some synergistic anti-leukemic effects. This review will summarize recent research findings and discuss the therapeutic potential of selected NRs in acute and chronic myeloid leukemia, focusing on RAR, VDR, PPAR, and retinoid X receptor (RXR). We believe that more mechanistic studies in this field will not only shed new lights on the roles of NRs in leukemia, but also further expand the clinical applications of existing therapeutic agents targeting NRs.
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Konopleva, Marina, Twee Tsao, Peter Ruvolo, Irina Stiouf, Zeev Estrov, Clinton E. Leysath, Shourong Zhao, et al. "Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia." Blood 99, no. 1 (January 1, 2002): 326–35. http://dx.doi.org/10.1182/blood.v99.1.326.
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It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML). CDDO-Me decreased the viability of leukemic cell lines, including multidrug resistant (MDR)-1–overexpressing, p53null HL-60-Dox and of primary AML cells, and it was 3- to 5-fold more active than CDDO. CDDO-Me induced a loss of mitochondrial membrane potential, induction of caspase-3 cleavage, increase in annexin V binding and DNA fragmentation, suggesting the induction of apoptosis. CDDO-Me induced pro-apoptotic Bax protein that preceded caspase activation. Furthermore, CDDO-Me inhibited the activation of ERK1/2, as determined by the inhibition of mitochondrial ERK1/2 phosphorylation, and it blocked Bcl-2 phosphorylation, rendering Bcl-2 less anti-apoptotic. CDDO-Me induced granulo-monocytic differentiation in HL-60 cells and monocytic differentiation in primary cells. Of significance, colony formation of AML progenitors was significantly inhibited in a dose-dependent fashion, whereas normal CD34+ progenitor cells were less affected. Combinations with ATRA or the RXR-specific ligand LG100268 enhanced the effects of CDDO-Me on cell viability and terminal differentiation of myeloid leukemic cell lines. In conclusion, CDDO-Me is an MDR-1– and a p53-independent compound that exerts strong antiproliferative, apoptotic, and differentiating effects in myeloid leukemic cell lines and in primary AML samples when given in submicromolar concentrations. Differential effects of CDDO-Me on leukemic and normal progenitor cells suggest that CDDO-Me has potential as a novel compound in the treatment of hematologic malignancies.
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Xie, Jingjing, Zhigang Lu, and Chengcheng Zhang. "KBP-1 Supports Acute Myeloid Leukemia Development." Blood 126, no. 23 (December 3, 2015): 1378. http://dx.doi.org/10.1182/blood.v126.23.1378.1378.
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Abstract Novel targets are needed to develop effective therapeutic approaches to treat acute myeloid leukemia (AML). We have developed a systematic strategy to identify factors important for leukemia development. We first use clinical databases to identify plasma membrane proteins that have correlations with the clinical outcomes of leukemia patients. We then validate the functions of candidate proteins in leukemia models and compare these functions to those in normal cells. The signaling pathways identified provide candidate targets for development of therapeutic approaches. Using this approach, we previously identified several ITIM-containing receptors that support AML development. Here we performed an in silico analysis of the relationship between gene expression and the overall survival of AML patients using data from three independent databases: the TCGA AML database (https://tcga-data.nci.nih.gov/tcga/; n = 187), the GSE6891 database (n = 520), and the GSE10358 database (n = 91). Expression of genes encoding several factors, including IL2RA, GPR56, ACDY7, and kappa-binding protein-1 (KBP-1), inversely correlated with the overall survival of AML patients. We focused on the potential function of KBP-1 in AML development in this study. KBP-1 is a transcriptional regulator that was known to inhibit NF-kB signaling and enhance TGF-beta signaling. Previous studies indicated that KBP-1 inhibits teratoma growth. We detected significantly higher kbp-1 mRNA levels in cells from human AML cells than other leukemia cells. To study the potential function of KBP-1 in human leukemia, we inhibited the expression of KBP-1 by introducing lentivirus-encoded shRNAs into MV4-11 and THP-1 cells. The KBP-1 deficiency resulted in significantly decreased in vitro growth of these leukemia cells over time. To determine the underlying mechanism by which KBP-1 supports the growth of leukemia cells, we compared the cell cycle status, migration, and apoptosis of AML cells treated with these shRNAs or scrambled control shRNA. KBP-1-deficient cells had significantly increased levels of apoptosis compared to cells treated with the control shRNA (for example, 68% early apoptosis in KBP-1 knockdown MV4-11 cells vs 15% early apoptosis in control MV4-11 cells at 3 days after shRNA infection). These results indicate that KBP-1 supports leukemia cell growth by suppressing apoptosis. We further studied the function of KBP-1 in AML development using the KBP-1 knockout mice and retrovirus transplantation mouse models. Consistent with the results of KBP-1 knockdown in human leukemia cells, the knockout of KBP-1 in MLL-AF9 AML cells dramatically delayed AML development in mice, as determined by survival, flow cytometry, immunohistochemistry, and colony forming analyses. Serial transplantation of wild-type and KBP-1 knockout AML cells indicates that KBP-1 deficiency impaired the self-renewal of AML stem cells. We are working on elucidating the underlying mechanism by which KBP-1 supports the activity of AML stem cells. Together, this is the first demonstration of KBP-1 function in hematopoietic maligancies. KBP-1 is highly expressed by AML cells and its expression correlates with AML development. KBP-1 supports the survival of human AML cells and the activity of AML stem cells. The tumor-supportive role of KBP-1 in AML is different from its tumor-suppressive function in teratoma. Disclosures No relevant conflicts of interest to declare.
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Lam, Wilbur A., Michael J. Rosenbluth, and Daniel A. Fletcher. "Chemotherapy Exposure Decreases Leukemia Cell Deformability as Determined by Atomic Force Microscopy: Implications for Leukostasis in Acute Leukemia." Blood 108, no. 11 (November 1, 2006): 2359. http://dx.doi.org/10.1182/blood.v108.11.2359.2359.
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Abstract Leukostasis, a life-threatening complication of acute leukemia, occurs when leukemia cells obstruct the circulation of vital organs like the brain and lungs leading to intracranial hemorrhage or respiratory failure. Although the pathophysiology of leukostasis is poorly understood, an elevated concentration of circulating leukemia cells, pathologic adhesion, and decreased cell deformability are thought to play significant roles. Clinical deterioration can occur soon after chemotherapy is initiated, suggesting that chemotherapy itself may be a risk factor for leukostasis. To investigate the effects of chemotherapy on cell stiffness, we performed serial single cell deformability measurements with an atomic force microscope (AFM), a commonly used tool in nanoscience for imaging and characterizing mechanical properties of materials on a submicron level, and modified the AFM to operate in cell culture conditions at 37°C. Leukemia cells from patients with acute lymphoblastic leukemia and acute myeloid leukemia as well as leukemia cell lines were incubated with chemotherapeutic agents, and changes in cell stiffness were tracked over time with AFM as the cells underwent chemotherapy-induced cell death. In the presence of dexamethasone or daunorubicin, leukemia cells exhibited increases in stiffness by as much as two orders of magnitude. Cell stiffness appeared to increase before caspase activation and peaked after completion of cell death, and the rate at which cell stiffness increased was dependent on chemotherapy type. Stiffening with cell death was found to occur for all cell types and chemotherapies investigated and is due, at least in part, to dynamic changes in the actin cytoskeleton. This observed correlation between cell death and cell stiffening may partially explain why some leukemia patients develop leukostasis shortly after starting chemotherapy, and it suggests that leukocytoreduction should remain an important treatment for hyperleukocytosis in acute leukemia. Figure 1. Average apparent stiffness of dead (dark gray) leukemic cells exposed to chemotherapy is significantly higher compared to untreated (light gray) cells (n > 15, p < 0.05 for all comparisons of dead/untreated populations). (A) Primary ALL cells and lymphoid leukemic cell lines exposed to 1 μM dexamethasone (B) Primary AML and myeloid leukemic cell lines exposed to 1μM daunorubicin. Error bars are standard error. Figure 1. Average apparent stiffness of dead (dark gray) leukemic cells exposed to chemotherapy is significantly higher compared to untreated (light gray) cells (n > 15, p < 0.05 for all comparisons of dead/untreated populations). (A) Primary ALL cells and lymphoid leukemic cell lines exposed to 1 μM dexamethasone (B) Primary AML and myeloid leukemic cell lines exposed to 1μM daunorubicin. Error bars are standard error. Figure 2. Apparent stiffness of leukemic cells increases with progression of cell death. (A) A typical stiffness trace of a single M5 AML cell exposed to 1μM daunorubicin (circles). The apparent stiffness of a typical control cell remains relatively constant (triangles) and does not undergo apoptosis or cell death during the course of the experiment. Transition from open to filled shapres represents onset of cell death. Early apoptosis is defined as caspase 3 or 7 postivie staining and late apoptosis/dead is defined as Sytox Green (marker for cell membrane integrity loss) positive staining. (B) From the same patient sample, the average apparent stiffness of a population of late apoptotic/dead AML cells was significantly stiffer than early apoptopic cells and controls (n = 15, p< 0.05). Error bars are standard error. Figure 2. Apparent stiffness of leukemic cells increases with progression of cell death. (A) A typical stiffness trace of a single M5 AML cell exposed to 1μM daunorubicin (circles). The apparent stiffness of a typical control cell remains relatively constant (triangles) and does not undergo apoptosis or cell death during the course of the experiment. Transition from open to filled shapres represents onset of cell death. Early apoptosis is defined as caspase 3 or 7 postivie staining and late apoptosis/dead is defined as Sytox Green (marker for cell membrane integrity loss) positive staining. (B) From the same patient sample, the average apparent stiffness of a population of late apoptotic/dead AML cells was significantly stiffer than early apoptopic cells and controls (n = 15, p< 0.05). Error bars are standard error.
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Stone, Richard M., Margaret R. O'Donnell, and Mikkael A. Sekeres. "Acute Myeloid Leukemia." Hematology 2004, no. 1 (January 1, 2004): 98–117. http://dx.doi.org/10.1182/asheducation-2004.1.98.
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Abstract Advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) have not yet led to major improvements in disease-free and overall survival of adults with this disease. Only about one-third of those between ages 18–60 who are diagnosed with AML can be cured; disease-free survival is rare and current therapy devastating in older adults. In this chapter, challenges in the management of the adult with AML are discussed, including ongoing questions concerning the optimal choice of induction and postremission therapy such as the rationale for and role of allogeneic and autologous stem cell transplantation in a variety of settings, the special considerations pertaining to the older patient, and the development of new, so-called targeted therapies. In Section I, Dr. Richard Stone reviews state-of the-art therapy in AML in the era of change from a morphological to a genetically based classification system. Questions being addressed in ongoing randomized cooperative group trials include anthracycline dose during induction, the efficacy of drug-resistance modulators, and the utility of pro-apoptotic agents such as the anti-bcl-2 antisense oligonucloetide. Developmental therapeutics in AML include drug resistance modulation, anti-angiogenic strategies, immunotherapy, and signal transduction-active agents, particularly the farnesyl transferase inhibitors as well as those molecules that inhibit the FLT3 tyrosine kinase, activated via mutation in 30% of patients. In Section II Dr. Margaret O’Donnell discusses the role of stem cell transplantation in AML. Several advances including expanded donor pools, the movement toward peripheral blood stem cell collection, newer immunosuppressive drugs and antifungals, and particularly the advent of nonmyeloablative transplant have made the allogeneic option more viable. The subset-specific role for high-dose chemotherapy with autologous stem cell support and/or for allogeneic transplant in AML patients in first remission is outlined. Although preconceived notions about the role of transplant abound, the clinical data supporting a risk-adapted approach are covered. Finally, guidance concerning the use of nonmyeloablative or reduced-intensity allogeneic transplantation is provided. In Section III Dr. Mikkael Sekeres reviews the approach to the older patient with AML. Unique biological and therapeutic considerations make AML in this age group a vastly different disease than that in younger adults. The outcome data, including the role of specific anthracylines, hematopoietic growth factors, and drug-resistance modulators, are summarized. Communicating with older adults with AML and their families regarding selection of the optimal treatment strategy, often a stark choice between induction chemotherapy and palliative care, is covered.
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Dai, Yun, Shuang Chen, Li Wang, Xin-Yan Pei, Lora Kramer, Paul Dent, and Steven Grant. "Bortezomib Interacts Synergistically with Belinostat to Induce Apoptosis In Human Acute Myeloid and Lymphoid Leukemia Cells." Blood 116, no. 21 (November 19, 2010): 3266. http://dx.doi.org/10.1182/blood.v116.21.3266.3266.
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Abstract Abstract 3266 Previous studies have demonstrated interactions between histone deacetylase (HDAC) and proteasome inhibitors (PIs) in multiple myeloma, NHL, and CLL. However, exploration of this strategy in acute leukemias has been more limited. In this context, we have previously demonstrated that HDACIs activate the cytoprotective NF-κB pathway in acute myeloid leukemia (AML) cells, and that interruption of this process dramatically increases lethality. Such findings raise the possibility that PIs, which block degradation of the NF-κB-inhibitory protein IκBα, may act via an analogous mechanism in acute leukemias. Consequently, interactions between the clinically relevant pan-HDAC inhibitor belinostat (PXD-101) and the FDA-approved proteasome inhibitor bortezomib were evaluated in both continuously cultured cell lines and primary AML and acute lymphoid leukemia (ALL) samples. First, whereas each agent individually displayed only modest toxicity, co-treatment for 24 hr or 48 hr with low concentrations of bortezomib (3 - 5 nM) and belinostat (50 - 300 nM) led to pronounced increases in apoptosis in diverse human acute leukemia cell lines (e.g., AML, U937, HL-60, MV-4-11/Flt3-ITD; T-cell ALL, Jurkat; B-cell ALL, SEM). Interactions between these agents were determined to be synergistic by Median Dose Effect analysis. Significantly, equivalent interactions were observed in multiple primary AML (n = 4) and ALL (n = 3) blast specimens, while largely sparing normal CD34+ hematopoietic cells isolated from umbilical cord blood (n = 4), as determined by annexin V/PI, DiOC6, and/or 7-AAD uptake by flow cytometry. Western blot analysis demonstrated that co-exposure of primary leukemia blasts to bortezomib and belinostat resulted in marked increase in PARP cleavage, compared with each agent administrated alone. In addition, cell morphology exhibited classical features of apoptosis in primary acute leukemia blasts, but not in normal CD34+ cells, following combination treatment. Second, in both cell lines and primary blasts, administration of bortezomib resulted in accumulation of the phosphorylated (S32/S36) form of IκBα, accompanied by diminished belinostat-mediated hyperacetylation (K310) of RelA/p65. Bortezomib also blocked processing of the precursor p100 into the active p52, an event enhanced by co-treatment with belinostat. These results indicate that a regimen combining bortezomib and belinostat interrupts both canonical and non-canonical NF-κB signaling pathways in acute leukemia cells. Moreover, co-exposure to these agents diminished expression of NF-κB-dependent pro-survival proteins including Bcl-xL, XIAP, and SOD2, but not NF-κB-independent anti-apoptotic proteins such as survivin. Third, because the BH3-only Bcl-2 family pro-apoptotic protein Bim plays an important role in the lethality of PIs or HDACIs as single agents, the expression and functional role of Bim in bortezomib/belinostat interactions was examined. Notably, whereas treatment with marginally toxic concentrations of either agent alone clearly increased Bim protein levels, co-exposure of either leukemia cell lines or primary blasts to bortezomib and belinostat led to sharply increased Bim expression (particularly the BimEL isoform). Importantly, shRNA knock-down of Bim substantially attenuated lethality mediated by co-treatment with bortezomib and belinostat in both AML (U937) and ALL (Jurkat) cells, supporting the notion that up-regulation of Bim plays a critical role in anti-leukemic activity of the combination regimen. Lastly, exposure of cultured leukemia cells and primary blasts to belinostat ± bortezomib induced hyperacetylation of a-tubulin, indicating inhibition of HDAC6, a microtubule-associated deacetylase that regulates aggresome formation and cell survival in response to misfolded protein-induced stress. Together, these findings indicate that the regimen combining belinostat and bortezomib is highly active against human AML and ALL cells, including primary leukemic blasts, in association with perturbation in the balance between pro-survival (NF-κB-dependent) and pro-death (e.g., Bim) signals. They also suggest that this strategy warrants further attention in acute leukemias. Accordingly, a Phase I trial of belinostat and bortezomib in patients with refractory acute leukemia or MDS has recently been initiated. Disclosures: Off Label Use: Investigational use of belinostat and bortezomib.
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Hsieh, Yao-Te, Enzi Jiang, Jennifer Pham, Hye-Na Kim, Hisham Abdel-Azim, Sajad Khazal, Gesine Bug, Gabriele Spohn, Halvard Bonig, and Yong-Mi Kim. "VLA4 Blockade In Acute Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 3944. http://dx.doi.org/10.1182/blood.v122.21.3944.3944.
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Abstract Despite aggressive chemotherapy and early allogeneic transplantation, acute myeloid leukemia (AML) frequently relapses, so that over-all disease-free survival remains below 50%. Strategies to overcome the chemoresistance of relapse-initiating residual AML blasts are, therefore, warranted. Evidence has been provided that AML cells are sheltered from the insult of chemotherapeutic agents by interacting with bone marrow stroma. Integrin alpha4beta1 (VLA4) mediates adhesion of hematopoietic cells to bone marrow stroma cells and extracellular matrix and has been implicated in cell adhesion-mediated chemotherapy resistance. Based on the evidence thereof provided for ALL blasts, VLA4 is here proposed as a therapeutic target for refractory AML. For this purpose, VLA4 was functionally blocked in vitro and in vivo on patient-derived AML cells using an anti-functional humanized VLA4 antibody, Natalizumab (NZM). VLA4-positive (>90%) patient-derived (primary) AML cells were plated on immobilized human VCAM1 or human stromal cell line HS-5 and treated with control (IgG4) or Natalizumab (NZM) for 2 days. NZM de-adhered 94.0%±7.6 AML cells from its counter receptor VCAM-1, yet only 31.3%±13.8 from HS-5, indicating that stroma cells offer ligands for a wider panel of adhesion receptors besides VLA4. We tested also whether VLA4 blockade is beneficial against AML when combined with chemotherapy. For this purpose, primary AML cells were incubated with NZM and incubated on uncoated tissue culture plates or HS-5 stromal layers in the presence or absence of Ara-C (1µM) for two days. AML cells showed higher viability under Ara-C therapy when incubated with HS-5 cells compared to controls, indicating the chemoprotective effect of the stromal layer. The viability of the AML cells treated with combined Ara-C and NZM was similar to the controls, indicating that HS-5-mediated chemo-protection was completely abrogated by NZM. Significantly more AML cells treated with Ara-C+NZM stained AnnexinV+/7AAD- than after Ara-C+control Ig4 treatment (44.4%±5.6 vs. 29.8%±4.8, p=0.03) indicating increased apoptosis of AML cells. On its own, NZM did not induce apoptosis. Next, we tested NZM as a single agent in our NOD/SCIDIL2Rγ deficient (NSG) xenograft model of primary AML. Luciferase-labeled AML cells were intrafemorally injected into NSG mice (1x105 cells / mouse). NZM (5mg/kg) was given intraperitoneally once per week for 4 weeks. NZM-treated animals survived significantly longer than control Ig-treated animals (Median Survival Time, MST=107 days vs. MST=76 days; *p=0.008 by Log-rank Test.To determine effects of NZM on leukemia cell burden/distribution in different organs, primary AML cells were injected into NSG mice and allowed to engraft for 3 days, subsequently treated with a single dose of NZM or Ig control. 72 hours later, AML cell burden in femurs and spleens of NZM-treated animals was significantly decreased compared to control treated mice, however AML cells were not increased into the peripheral blood, so that whether leukemia cells were selectively killed ormobilized and then retained in non-hematopoietic organs remains to be determined. Further studies addressing molecular mechanisms of increased apoptosis after combined VLA4 blockade and chemotherapy are ongoing. Our data suggest that the paradigm of leukemia cell targeting by VLA4 blockade, previously demonstrated by us for ALL, can also be applied to AML. Disclosures: No relevant conflicts of interest to declare.
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Opydo-Chanek, Małgorzata, Iwona Cichoń, Agnieszka Rak, Elżbieta Kołaczkowska, and Lidia Mazur. "The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells." Investigational New Drugs 38, no. 6 (May 4, 2020): 1664–76. http://dx.doi.org/10.1007/s10637-020-00931-4.
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Summary One of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration.
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Kogan, Scott C., Diane E. Brown, David B. Shultz, Bao-Tran H. Truong, Valerie Lallemand-Breitenbach, Marie-Claude Guillemin, Eric Lagasse, Irving L. Weissman, and J. Michael Bishop. "Bcl-2 Cooperates with Promyelocytic Leukemia Retinoic Acid Receptor α Chimeric Protein (Pmlrarα) to Block Neutrophil Differentiation and Initiate Acute Leukemia." Journal of Experimental Medicine 193, no. 4 (February 19, 2001): 531–44. http://dx.doi.org/10.1084/jem.193.4.531.
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The promyelocytic leukemia retinoic acid receptor α (PMLRARα) chimeric protein is associated with acute promyelocytic leukemia (APL). PMLRARα transgenic mice develop leukemia only after several months, suggesting that PMLRARα does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRARα to initiate leukemia. Evaluation of preleukemic animals showed that whereas PMLRARα alone modestly altered neutrophil maturation, the combination of PMLRARα and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRARα and BCL-2 than in mice expressing PMLRARα alone, and all mice expressing both transgenes succumbed to leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRARα to initiate APL.
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Lück, Sonja C., Annika C. Russ, Konstanze Döhner, Ursula Botzenhardt, Domagoj Vucic, Kurt Deshayes, Richard F. Schlenk, Hartmut Döhner, Simone Fulda, and Lars Bullinger. "Deregulated Apoptotic Pathways Point to Effectiveness of IAP Inhibitor Therapy in Acute Myeloid Leukemia." Blood 114, no. 22 (November 20, 2009): 1275. http://dx.doi.org/10.1182/blood.v114.22.1275.1275.
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Abstract Abstract 1275 Poster Board I-297 Core binding factor (CBF) leukemias, characterized by translocations t(8;21) or inv(16)/t(16;16) targeting the core binding factor, constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, 40-50% of patients relapse, and the current classification system does not fully reflect the heterogeneity existing within the cytogenetic subgroups. Therefore, illuminating the biological mechanisms underlying these differences is important for an optimization of therapy. Previously, gene expression profiling (GEP) revealed two distinct CBF leukemia subgroups displaying significant outcome differences (Bullinger et al., Blood 2007). In order to further characterize these GEP defined CBF subgroups, we again used gene expression profiles to identify cell line models similar to the respective CBF cohorts. Treatment of these cell lines with cytarabine (araC) revealed a differential response to the drug as expected based on the expression patterns reflecting the CBF subgroups. In accordance, the cell lines resembling the inferior outcome CBF cohort (ME-1, MONO-MAC-1, OCI-AML2) were less sensitive to araC than those modeling the good prognostic subgroup (Kasumi-1, HEL, MV4-11). A previous gene set enrichment analysis had identified the pathways Caspase cascade in apoptosis and Role of mitochondria in apoptotic signaling among the most significant differentially regulated BioCarta pathways distinguishing the two CBF leukemia subgroups. Thus, we concluded that those pathways might be interesting targets for specific intervention, as deregulated apoptosis underlying the distinct subgroups should also result in a subgroup specific sensitivity to apoptotic stimuli. Therefore, we treated our model cell lines with the Smac mimetic BV6, which antagonizes inhibitor of apoptosis (IAP) proteins that are differentially expressed among our CBF cohorts. In general, sensitivity to BV6 treatment was higher in the cell lines corresponding to the subgroup with good outcome. Time-course experiments with the CBF leukemia cell line Kasumi-1 suggested a role for caspases in this response. Interestingly, combination treatment of araC and BV6 in Kasumi-1 showed a synergistic effect of these drugs, with the underlying mechanisms being currently further investigated. Based on the promising sensitivity to BV6 treatment in some cell lines, we next treated mononuclear cells (mostly leukemic blasts) derived from newly diagnosed AML patients with BV6 in vitro to evaluate BV6 potency in primary leukemia samples. Interestingly, in vitro BV6 treatment also discriminated AML cases into two distinct populations. Most patient samples were sensitive to BV6 monotherapy, but about one-third of cases were resistant even at higher BV6 dosage. GEP of BV6 sensitive patients (at 24h following either BV6 or DMSO treatment) provided insights into BV6-induced pathway alterations in the primary AML patient samples, which included apoptosis-related pathways. In contrast to the BV6 sensitive patients, GEP analyses of BV6 resistant cases revealed no differential regulation of apoptosis-related pathways in this cohort. These results provide evidence that targeting deregulated apoptosis pathways by Smac mimetics might represent a promising new therapeutic approach in AML and that GEP might be used to predict response to therapy, thereby enabling novel individual risk-adapted therapeutic approaches. Disclosures Vucic: Genentech, Inc.: Employment. Deshayes:Genentech, Inc.: Employment.
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Pomares, Helena, Claudia M. Palmeri, Daniel Iglesias-Serret, Cristina Moncunill-Massaguer, José Saura-Esteller, Sonia Núñez-Vázquez, Enric Gamundi, et al. "Targeting prohibitins induces apoptosis in acute myeloid leukemia cells." Oncotarget 7, no. 40 (August 17, 2016): 64987–5000. http://dx.doi.org/10.18632/oncotarget.11333.
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Ball, Somedeb, and Gautam Borthakur. "Apoptosis targeted therapies in acute myeloid leukemia: an update." Expert Review of Hematology 13, no. 12 (December 1, 2020): 1373–86. http://dx.doi.org/10.1080/17474086.2020.1852923.
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Pigneux, Arnaud, Maïalen Uhalde, François X. Mahon, Francis Lacombe, Vincent Praloran, Noel-Jean Milpied, and Francis Belloc. "Triptolide Cooperates with Cytarabine To Induce Apoptosis in Acute Myeloid Leukemia." Blood 108, no. 11 (November 16, 2006): 1902. http://dx.doi.org/10.1182/blood.v108.11.1902.1902.
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Abstract Triptolide, a diterpene triepoxide isolated from the Chinese herb Tripterygium wilfordii Hook.f, has shown antitumor activity in a broad range of solid tumors and on leukemic cells in vitro. Here, we examined its pro-apoptotic effects on THP1 myeloid cell line and primay AML blasts in association with cytarabine. THP1 cells were treated with increasing concentrations of Ara-C in the presence or not of Triptolide (5 ng/ml). Apoptosis was measured by flow cytometry at the mitochondrial level by using the ΔΨm sensitive probe DiOC6(3). This low dose of Triptolide did not induce any apoptosis in 24 hrs. However, it significantly increased the apoptosis induced by Ara-C in the range 0.1–2 μg/ml (p<0.001) (figure 1). At 48 hrs, this cooperative effect was observed for lower doses of Ara-C (0.05–0.1 μg/ml)(figure 2). Fig. 1 Fig. 1. Fig. 2 Fig. 2. When measuring the IκB content by western blot, although triptolide alone was found able to decrease IκB (p<0.05), there was no effect on the IκB content of Ara-C-treated cells. Similarly, no effect of the Ara-C/Triptolide association was found in the DNA binding activity of NFκB. The DNA synthesis activity was measured by flow cytometry using the BrdUrd method and a dose dependent DNA synthesis inhibition was found with Triptolide from 2 to 20 ng/ml. Moreover, the association of 5 ng/ml Triptolide with 0.05 or 0.1 μg/ml of Ara-C showed an increase in the DNA synthesis inhibition as compared with both drugs separately. However, while Ara-C induced an accumulation of cells in the S compartment of the cell cycle, the cell cycle distribution was not significantly altered by Triptolide alone, suggesting that this drug induced also a slowing down during all the cell cycle. The association Triptolide/Ara-C was also investigated in vitro on primary blast cells from 26 AML patients. The blood or bone marrow mononuclear cells were cultured for 48 to 72 hrs in the presence of a cytokine cocktail (Stem α.4B) to recruit the cells into the cell cycle. The samples were then treated with 7.5 ng/ml Triptolide, 0.05 or 0.1 ng/ml Ara-C or both drugs in combination for 24 and 48 hrs. Apoptosis was measured by flow cytometry, using FITC-Annexin V. The blast cells were discriminated on the basis of their low CD45 expression. The combination of both drugs yielded a percentage of apoptotic cells that was significantly higher than each drug administered separately (p<0.05). These results show that low concentrations of Triptolide which were not shown to induce apoptosis by themselves were able to potentiate the pro-apoptotic and anti-proliferative effects of Ara-C. The potentiation by triptolide of the antileukemic activity of cytarabine in vitro warrants further clinical investigations for the treatment of AML patients, specially in elderly patients in which low-dose cytarabine treatment could be improved by an association with Triptolide.
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Mirabilii, Simone, Maria Rosaria Ricciardi, Matteo Allegretti, Roberto Licchetta, Martina Vincenzi, Raffaella Nicolai, Robin Foà, and Agostino Tafuri. "Modulation Of The Glycolytic Metabolism In Acute Myeloid Leukemia Cells." Blood 122, no. 21 (November 15, 2013): 5045. http://dx.doi.org/10.1182/blood.v122.21.5045.5045.
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Abstract Glycolysis is the central axis of cellular metabolism. The cancer cell bioenergetic status heavily relies on high glycolytic rates, even in aerobic conditions, thus sustaining the expensive processes of cell growth and proliferation. Growing evidences show that signaling aberrations - especially those involving PI3K/Akt/mTOR, HIF1a, Ras/Raf/MEK/ERK - are strictly connected to the establishment of a pro-glycolytic metabolism, through a multi-level crosstalk between proteins and metabolites that contribute to the acquisition of an energetic background granting a proliferative advantage. Here we investigated the glycolytic rate of resting and activated normal peripheral blood lymphocytes (NPBLs) and of acute myeloid leukemia (AML) cell lines. In an attempt to modulate the cellular metabolism for therapeutic intervention, we tested the following compounds that directly interfere with major metabolic or signaling pathways: dichloroacetate (DCA), a glycolysis inhibitor; aminooxyacetate (AOA), a glutaminolysis inhibitor; ST1326 (kindly given by Sigma-Tau), a fatty acid oxidation (FAO) inhibitor; and the MEK inhibitor PD0325901 (Selleck Chemicals). The cytotoxic drug effects were evaluated on two human leukemia cell lines, U937 and OCI-AML3, characterized by PI3K/Akt/mTOR and Ras/Raf/MEK/ERK hyperactivation, respectively. Cell counts, apoptosis (AnnexinV), glucose and lactate levels (GEM4000, Instrumentation Laboratory, UK) were measured. The glucose consumption rate (GCR) and lactate production rate (LPR) were calculated according to Li et al. (Biotechol. Appl. Biochem., 2005, 42, 73-80). Resting NPBLs were characterized by a very low glycolytic rate, according to their quiescent state, while cultured phytohemagglutinin-activated NPBLs displayed a remarkable increase in glycolytic rate: the GCR calculated over 72 hours showed a 25 fold-increase, while LPR had a of 10 fold-increase. Acute myeloid cell lines showed a high glucose catabolism: at 24h the U937 cell line, compared to activated NPBLs, had a 6.7 fold higher GCR, while the OCI-AML3 cell line showed a 4-fold increase. DCA exposure showed at 24h no detectable effect on GCR, LPR and apoptosis at concentrations ranging from 0.01 to 0.5mM on the U937 cell line. Apoptosis effects were detected only at higher concentrations: AnnexinV positive cells increased from 4.3 ± 1.5 (control) to 62.8 ± 16.4 (5mM) and 88.1 ± 16.8 (10mM). Exposure to AOA (24h at 1000µM) slightly increased GCR (1.23-fold) and LPR (1.22-fold) on U937 cells, followed by apoptotic effects at 72h: from 6.24 ± 4.2 (control) to 10.4 ± 0.8 at 100µM to 83.5 ± 0.7 at 1000µM. The FAO inhibitor ST1326 (10µM at 24h) induced a 3-fold increase of GCR in the U937 cell line. Apoptotic effects were seen in the U937 cells at 72h, from 5.0 ± 2.3 (control) to 35.9 ± 5.7 at 5µM to 64.1 ± 20.5 at 10µM. Conversely, GCR, LPR and apoptosis did not change on the OCI-AML3 line following ST1326 exposure. The MEK inhibitor PD0325901 caused a reduction of GCR and LPR on OCI-AML3 cells (6-fold GCR decrease, 2-fold LPR decrease at 100nM); apoptosis at 72h ranged from 6.3 ± 1.1 (control) to 15.5 ± 3.9 at 10nM to 45.3 ± 0.1 at 100nM. The U937 cells proved resistant to this compound, showing no metabolic perturbation and absence of apoptotic effects. In summary, this study indicates that exploiting the metabolism as a target for therapeutic intervention appears to be a promising new strategy. In fact, the inhibition of glycolysis by blocking either the activity of the enzymes that directly participate to the metabolic pathway or key components of cell signaling has proven to be effective in inducing apoptosis in AML cells. Interestingly, the opposing response to the various compounds observed in the two AML models may likely reflect their divergent signaling network, prompting further studies to evaluate the correlation between aberrant signal transduction pathways and peculiar metabolic profiles. Disclosures: Nicolai: Sigma Tau Pharmaceuticals: Employment.
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Hess, Corine J., Johannes Berkhof, Fedor Denkers, Gert J. Ossenkoppele, Peter J. Valk, Ruud Delwel, Quinten Waisfisz, and Gerrit Jan Schuurhuis. "New Insights in Mechanims Involved in Apoptosis Resistance in Acute Myeloid Leukemia." Blood 106, no. 11 (November 16, 2005): 1215. http://dx.doi.org/10.1182/blood.v106.11.1215.1215.
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Abstract Defects in apoptotic mechanisms play an important role in chemotherapy resistance in AML, resulting in either refractoriness or high levels of Minimal Residual Disease (MRD) ultimately leading to relapse. For that reason the search for prognostic markers has focused on genes involved in apoptosis. At present the general concept encompasses a balance between pro- and anti apoptotic family members, but few studies have addressed large sets of genes. We tried to identify gene-profiles with maximal predictive power for patient survival by simultaneous quantification of 35 apoptosis related target sequences. For this purpose we have used the Reverse Transcriptase-Multiplex Ligation dependent Probe Amplification (RT-MLPA, Hess, Leukemia2004; 18:1981) method in viable (7AAD− /AnnexinV-) blasts of 120 newly diagnosed AML. Eight out of 35 genes predicted for poor survival and these surprisingly contained both anti-apoptotic (n=4) and pro-apoptotic (n=4) genes. These were used to compose 3-gene-signatures. High gene expression in these signatures predicted for poor survival in 40 out of the 56 possible combinations, with no preference for the anti-apoptosis genes. This is quite unlike the current concepts and evoked the idea that a more general mechanism is responsible for defective apoptosis regulation. To identify such mechanism we extracted the latent variable structure from our dataset using Principal Component Regression analysis. Several components, each containing the contribution of all 35 genes, were identified; of these, the fourth component was predictive for achievement of complete remission (CR) (p=0.009, B(exp)=2.47). Of all genes, the anti-apoptotic gene XIAP had the highest impact on this component. Its negative impact on CR rate in AML is in agreement with other reports. Most importantly, 33/35 genes had a positive impact on the main component. This component turned out to be highly associated with the median expression of all 35 genes present in each sample (p=0.0005, R=0.664). In turn, high median gene expression was predictive for poor OS (N=120, p=0.01). In agreement with our hypothesis this points to activation/deregulation of the complete apoptosis pathways instead of deficiencies in individual gene expression. To confirm this observation we have cross-validated our MLPA findings using a published micro-array dataset (N Engl J Med2004; 350:16). Fifteen patients were present in both datasets and showed positive correlation in 21/24 parallel gene sequences. With the exclusion of these 15 patients, in the array data too, both increased pro and anti apoptotic gene expression correlated with poor prognosis. For improvement of predictive strength of gene expression on patient survival, we have maximized the number of genes under analysis (N=33). To increase the distinctive power of each gene, we dichotomized our data based on arbitrary thresholds (10%, 50%, 90%) in the ranges of individual gene expression. This pathway approach showed in both methods that expression of multiple genes above the 90% threshold is associated with short survival. For MLPA this was also found at lower thresholds of 50% or 10%. In conclusion, with the use of the novel and very sensitive RT-MLPA technique we have identified general deregulation of the apoptosis cascade as a cause of treatment failure in AML.
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Kojima, Kensuke, Steven M. Kornblau, Vivian Ruvolo, Seshagiri Duvvuri, Richard E. Davis, Min Zhang, Zhiqiang Wang, et al. "Prognostic Impact and Targeting of CRM1 in Acute Myeloid Leukemia." Blood 120, no. 21 (November 16, 2012): 870. http://dx.doi.org/10.1182/blood.v120.21.870.870.
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Abstract Abstract 870 p53 is a transcription factor that prevents abnormal cell growth. Cellular levels of p53 are critically regulated by MDM2, which is frequently over-expressed in AML. Nutlin-3a disrupts MDM2-p53 interaction, increases cellular levels of p53 in both nucleus and cytoplasm, and activates p53 signaling in cells. p53 status is the major determinant of response to MDM2 inhibitors. p53 is shuttled between the nucleus and the cytoplasm, and CRM1 mediates its nuclear export. Karyopharm Therapeutics has developed novel, potent and irreversible small molecule selective inhibitors of CRM1. We hypothesized that CRM1 inhibition would enhance the nuclear activity of p53, thereby enhancing p53-mediated transcription-dependent apoptotic signaling in AML. We measured CRM1 expression in primary AML samples and investigated if blockade of nuclear export of p53 by CRM1 inhibition would enhance MDM2 inhibitor-induced apoptosis in AML. CRM1 expression was investigated in 511 patient AML samples using a validated robust reverse-phase protein array. Higher levels of CRM1 were associated with higher marrow and peripheral blast percentages (P < 0.00001). Expression was lower in those with favorable cytogenetics compared to those with intermediate or unfavorable cytogenetics (P = 0.029). CRM1 levels were higher in patients with FLT3 mutations (P = 0.003). In 3-way correlation (using distance weighted least squares), there was a clear interaction with p53 levels being highest when CRM1 was high and MDM2 levels were low. Overall survival progressively worsened as CRM1 levels increased, with median survival of 66 weeks for those with CRM1 expression in the lowest third, 47 weeks for middle third and 37 weeks in the highest third (P = 0.007). CRM1 levels did not affect remission duration (P = 0.33). The CRM1 inhibitor KPT-185 exhibited dose-dependent anti-proliferative and cytotoxic activity in AML cell lines, as evidenced by low IC50 values and high Annexin V positivity (= low ED50 values). IC50 values for wild-type p53 cells ranged from 27 to 38 nM, and for mutant p53 cells from 48 to 112 nM, suggesting that KPT-185 potently inhibits AML cell growth largely independent of p53. In contrast, apoptosis induction by KPT-185 was much more prominent in p53 wild-type than in p53-defective cells: ED50 values for Annexin V induction were 150, 90 and 85 nM in p53 wild-type and > 1000 nM in 5 of 6 p53 mutant cell lines. Stable p53 knockdown (> 90% efficiency) rendered AML cells resistant to KPT-induced apoptosis. KPT-185 induced p53 target genes TP53I3, GDF15, MDM2 and ZMAT3 partially in a p53-dependent manner. Hence, p53 was identified as major determinant of CRM1 inhibition-induced apoptosis in AML. MDM2-inhibitor Nutlin-3a induced p53 in both nucleus and cytoplasm, while CRM1 inhibition accumulated p53 in the nucleus. Treatment with KPT-185 or Nutlin-3a caused time-dependent increase in cellular p53 levels. The KPT-185/Nutlin-3a combination induced p53 more efficiently than the individual agents by accumulating p53 exclusively in the nucleus, and synergistically induced apoptosis and cell death. p53 knockdown abrogated these synergistic effects. In primary AML cells, both KPT-185 (24.7 – 36.7% Annexin V) and Nutlin-3a (13.6 – 59.8%) induced apoptosis in a dose-dependent manner. Importantly, both KPT-185 and Nutlin-3a induced apoptosis in CD34+CD38- progenitor cell populations as effectively as they did in bulk AML cells, suggesting high sensitivity of CD34+CD38- cells to CRM1 inhibition and MDM2 inhibition. KPT-185 and Nutlin-3a synergized in the induction of apoptosis in both bulk and CD34+CD38- AML progenitor cells: combination index (CI) values were 0.26 (bulk) and 0.30 (CD34+CD38-) for ED50 and 0.93 (bulk) and 0.46 (CD34+CD38-) for ED75, indicating highly synergistic (CI < 1) efficacy in apoptosis induction. The relation between p53 status and sensitivity to Nutlin-induced apoptosis has been well established. Nutlin-resistant samples were much less sensitive to KPT-185 than Nutlin-sensitive cases (12.2 ± 0.06 % versus 30.9 ± 0.04 % Annexin V, P < 0.05). Synergistic induction of apoptosis was not observed in normal cord blood CD34+CD38- cells. Collectively, CRM1 inhibition offers a novel therapeutic strategy for AML that mostly retains wild-type p53. We propose to develop novel combinatorial approaches for the therapy of AML, aimed at maximal activation of p53 and apoptosis signaling by concomitant MDM2 and CRM1 inhibition. Disclosures: Shacham: Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment. Andreeff:Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other.
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Yang, Mingzhen, Xiaoyu Zhang, Zhenqi Huang, Qingsheng Li, Lin Wang, and Qinhua Liu. "The Apoptosis of Acute Myeloid Leukemia Cell Line (SHI-1 cells) Induced by Bortezomib In Vitro." Blood 116, no. 21 (November 19, 2010): 4382. http://dx.doi.org/10.1182/blood.v116.21.4382.4382.
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Abstract Abstract 4382 Background: The proteasome plays a critical role in the regulation of many cellular processes, including the cell cycle and tumor growth. The proteasome inhibitor Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we investigated the induction of apoptosis by proteasome inhibitor Bortezomib in human acute myeloid leukemia (AML) cell lines SHI-1 cells and try to explore the mechanism of anti-leukemia. Method: We incubated SHI-1 leukemic cells with different concentration of bortezomib. cell proliferation was detected with MTT, apoptosis was measured by FCM, the protein expression of PI3K and p-Akt were determined by Western blot. Result: 0.5ug/ml bortezomib suppressed SHI-1 cells proliferation and induced SHI-1 cells apoptosis after incubated 24hr, 100ug/ml bortezomib suppressed 61.7% SHI-1 cells proliferation. Apoptosis increased obviously with the increasing bortezomib concentration and the culture time, about 39.77% SHI-1 cells were apoptosis when bortezomib concentration was 100ug/ml, the leukemia cell apoptosis was significant at 150ng/ml bortezomib, the protein expression of PI3K, and p-Akt gradually declined with bortezomib concentration increasing, The protein expression of PI3K and p-Akt in SHI-1 cells decreased 50.6% and 71.6% respectively at 100ug/ml bortezomib for 48hr.when 150ng/ml bortezomib incubated with leukemia cells for 24 hours, The protein expression of PI3K and p-Akt were lowest. Conclusion: Bortezomib could inhibit SHI-1 cells proliferation and induce leukemia cells apoptosis, and could down-regulate the expression of PI3K and p-Akt significantly, this might be the one of mechanisms that bortezomib induce SHI-1 cells apoptosis, we presume that bortezomib inhibit proliferation of acute myelogenous leukemia cells through effect of PI3K/Akt signaling pathways. Disclosures: No relevant conflicts of interest to declare.
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Radomska, Hanna S., Finith Jernigan, Sohei Nakayama, Susan E. Jorge, Lijun Sun, Daniel G. Tenen, and Susumu S. Kobayashi. "A Cell-Based High-Throughput Screening for Inducers of Myeloid Differentiation." Journal of Biomolecular Screening 20, no. 9 (June 24, 2015): 1150–59. http://dx.doi.org/10.1177/1087057115592220.
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Recent progress of genetic studies has dramatically unveiled pathogenesis of acute myeloid leukemia (AML). However, overall survival of AML still remains unsatisfactory, and development of novel therapeutics is required. CCAAT/enhancer binding protein α (C/EBPα) is one of the crucial transcription factors that induce granulocytic differentiation, and its activity is perturbed in human myeloid leukemias. As its reexpression can induce differentiation and subsequent apoptosis of leukemic cells in vitro, we hypothesized that chemical compounds that restore C/EBPα expression and/or activity would lead to myeloid differentiation of leukemic cells. Using a cell-based high-throughput screening, we identified 2-[( E)-2-(3,4-dihydroxyphenyl)vinyl]-3-(2-methoxyphenyl)-4(3H)-quinazolinone as a potent inducer of C/EBPα and myeloid differentiation. Leukemia cell lines and primary blast cells isolated from human patients with AML treated with ICCB280 demonstrated evidence of morphological and functional differentiation, as well as massive apoptosis. We performed conformational analyses of the high-throughput screening hit compounds to postulate the spatial requirements for high potency. Our results warrant a development of novel differentiation therapies and significantly affect care of patients with AML with unfavorable prognosis in the near future.
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San José-Enériz, Gimenez-Camino, Agirre, and Prosper. "HDAC Inhibitors in Acute Myeloid Leukemia." Cancers 11, no. 11 (November 14, 2019): 1794. http://dx.doi.org/10.3390/cancers11111794.
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Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.
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Rosen, David B., M. D. Minden, Santosh Putta, Todd Covey, Ying W. Huang, Alessandra Cesano, and Wendy J. Fantl. "Classification of Acute Myeloid Leukemia (AML) Based On Apoptosis and Myeloid Signaling Networks." Blood 114, no. 22 (November 20, 2009): 325. http://dx.doi.org/10.1182/blood.v114.22.325.325.
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Abstract Abstract 325 Background: Acute Myeloid Leukemia (AML) is the most common myeloid malignancy in adults and represents an aggressive disease with significant biological and clinical heterogeneity. Currently, cytogenetics and molecular changes are used to inform treatment strategies. However a wide range of clinical responses are observed in these patient subgroups necessitating alternative methodologies to provide information that could inform clinical decisions for AML disease management. Since the net result of the cytogenetic and molecular changes is necessarily a functional alteration of proteins within signal transduction networks the current study was undertaken to understand the diversity of signaling responses in AML patient samples. Critically, in these studies treatment of samples with a variety of input stimuli allowed intracellular phospho-signaling and apoptosis network properties to be revealed that would otherwise remain unseen in resting cells. Objectives: Single cell network profiling (SCNP) using muliparameter flow cytometry was used to identify intracellular pathway responses to treatment with myeloid cytokines and growth factors in addition to apoptosis-inducing agents in individual AML patients. Identification of unique signaling profiles in patient sample sub-groups may inform the choice of specific therapeutic regimens. Methods: JAK/STAT, PI3K/S6 and apoptosis signaling pathways were measured after in vitro exposure of 34 diagnostic non-M3 AML samples to a panel of myeloid growth factors (e.g FLT3L, SCF), cytokines (e.g G-CSF, GM-CSF) interleukins (e.g IL-6, IL-27) and apoptosis-inducing agents (etoposide, staurosporine). Samples were processed for cytometry by paraformaldehyde/methanol fixation and permeabilization followed by incubation with fluorochrome-conjugated antibody cocktails that recognize both cell surface proteins to delineate cell subsets in addition to intracellular signaling molecules. Results: JAK/STAT and PI3K/S6 signaling responses to individual modulators revealed a range of activity in these pathways within individual patients. Analysis of JAK/STAT and PI3K/S6 pathways across individual patient samples identified subgroups of samples with distinct pathway profiles: A) high JAK/STAT activity, B) high PI3K/S6 activity, C) high activity in both pathways, and D) low activity in both pathways. In vitro exposure of samples to staurosporine and etoposide revealed three distinct “apoptosis” profiles: 1) Staurosporine Refractory 2) Etoposide Refractory and samples that were 3) Apoptosis Competent in response to both these agents. In this study, elevated PI3K/S6 pathway activity and elevated IL-27/IL-6 induced JAK/STAT pathway activity was associated with in vitro refractoriness to apoptosis inducing agents. Analysis of JAK/STAT, PI3K/S6 and Apoptosis pathway activities characterized biologically distinct patient-specific signatures, even within cytogenetically and phenotypically uniform patient subgroups. Notable were differences in signaling profiles between samples from different patients and in cell subpopulations within the same sample. Conclusions: SCNP revealed a range of signaling responses within AML samples consistent with the heterogeneity of the disease. The data suggest the importance of characterizing and tracking signaling profiles within the subpopulations of an AML sample over time and in response to therapeutic pressure with the aim of guiding the choice of a targeted agent to be used alone or in combination with chemotherapy to improve patient response rates. Disclosures: Rosen: Nodality, Inc.: Employment, Equity Ownership. Putta:Nodality, Inc.: Employment, Equity Ownership. Covey:Nodality, Inc.: Employment, Equity Ownership. Huang:Nodality Inc.: Employment, Equity Ownership. Cesano:Nodality Inc.: Employment, Equity Ownership. Fantl:Nodality, Inc.: Employment, Equity Ownership.
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Tallman, Martin S., D. Gary Gilliland, and Jacob M. Rowe. "Drug therapy for acute myeloid leukemia." Blood 106, no. 4 (August 15, 2005): 1154–63. http://dx.doi.org/10.1182/blood-2005-01-0178.
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AbstractAlthough improvement in outcomes has occurred in younger adults with acute myeloid leukemia (AML) during the past 4 decades, progress in older adults has been much less conspicuous, if at all. Approximately 50% to 75% of adults with AML achieve complete remission (CR) with cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only approximately 20% to 30% of the patients enjoy long-term disease survival. Various postremission strategies have been explored to eliminate minimal residual disease. The optimal dose, schedule, and number of cycles of postremission chemotherapy for most patients are not known. A variety of prognostic factors can predict outcome and include the karyotype of the leukemic cells and the presence of transmembrane transporter proteins, which extrude certain chemotherapy agents from the cell and confer multidrug resistance and mutations in or over expressions of specific genes such as WT1, CEBPA, BAX and the ratio of BCL2 to BAX, BAALC, EVI1, KIT, and FLT3. Most recently, insights into the molecular pathogenesis of AML have led to the development of more specific targeted agents and have ushered in an exciting new era of antileukemia therapy. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyl transferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, Fms-like tyrosine kinase 3 (FLT3) inhibitors, and apoptosis inhibitors.
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Jianbiao Zhou, Jessie Yiying Quah, Yvonne Ng, Jing-Yuan Chooi, Sabrina Hui-Min Toh, Baohong Lin, Tuan Zea Tan, et al. "ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia." Haematologica 105, no. 9 (November 7, 2019): 2286–97. http://dx.doi.org/10.3324/haematol.2019.230482.
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Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients.
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Chen, Rong, Bonnie Leung, Yuling Chen, and William Plunkett. "Activities and Mechanism Based Combinations Of Omacetaxine In Acute Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 1288. http://dx.doi.org/10.1182/blood.v122.21.1288.1288.
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Abstract Omacetaxine, an inhibitor of translation, was recently granted accelerated approval for the treatment of chronic myeloid leukemia (CML). Omacetaxine blocks translation elongation by competing with the incoming aminoacyl-tRNAs for binding to the A-site cleft in the peptidyl-transferase center. Our previous studies showed that by transiently inhibiting translation, omacetaxine reduced the expression of the key, short-lived oncoproteins Bcr/Abl and Mcl-1, leading to cell death in the CML cells. This action sensitized the cells to the Abl kinase inhibitor and killed the CML cells synergistically. Further, as omacetaxine acts in a different mechanism than the Abl kinase inhibitors, it overcame resistance to TKI that was associated with kinase domain mutations. These studies paved the foundation for the clinical development of omacetaxine in CML. We also demonstrated that omacetaxine was active in chronic lymphocytic leukemia by translational inhibition of Mcl-1 expression. In contrast to normal tissues, the fact that the leukemia cells are critically dependent on the oncogene activity for survival provided a biologic context for a positive therapeutic index. As the biological features of acute myeloid leukemia (AML) rely largely on the overexpressed oncoproteins or constitutively activated kinases, we hypothesized that omacetaxine would have therapeutic benefit in AML either alone or in mechanism based combinations. To test this hypothesis, first, we compared omacetaxine to AC220, a potent FLT3 inhibitor, in AML cell lines OCI-AML3 and MV4-11. OCI-AML3 cells harbor the signature mutation of NPM1, whereas MV4-11 is a widely used model for the internal tandem duplications of FLT3 (FLT3-ITD), a common FLT3 mutation that constitutively activates the receptor tyrosine kinase. AC220 was selectively toxic to the MV4-11 cells, but had no effect on the viability of OCI-AML3. This is consistent with the biological context of MV4-11, but not OCI-AML3, that is addicted to the sustained activity of FLT3 for survival. In contrast, omacetaxine induced apoptosis in both cell lines with IC50s less than 100 nM. Protein synthesis was inhibited in both lines, measured by the incorporation of tritiated leucine. Apoptosis was induced rapidly within 24 h by omacetaxine, whereas AC220 required 72 h to kill the leukemia cells. These results indicated a common dependence on the continued protein synthesis in the AML lines, suggesting a potentially broad application of omacetaxine in AML patients with diverse genetic backgrounds. Over-expression of the anti-apoptotic protein Mcl-1 is associated with AML disease maintenance and resistant to therapy. Both Mcl-1 and FLT3 turn-over rapidly and are vulnerable targets of transient translation inhibition. Immunoblots showed that omacetaxine reduced the levels of both FLT3 and Mcl-1 in the MV4-11 cells. This activity augmented the effect of AC220 on FLT3 kinase, and induced synergistic apoptosis. Same synergistic combination was observed with omacetaxine and sunitinib, an inhibitor of FLT3, KIT and PDGF-R. Dose reduction index derived from these analyses showed that omacetaxine greatly potentiated the activity of both AC220 and sunitinib, resulting in profound apoptosis. Both Bcl-2 and Mcl-1 are pro-survival proteins that regulate apoptosis by interacting with the BH3 motifs of their pro-apoptotic partners. BH3 mimetics, such as ABT-199, bind with high affinity to Bcl-2 and block this interaction, but not to Mcl-1. Resistance to BH3 mimetics in AML cells is associated with upregulation of Mcl-1. Since ABT-199 inhibits Bcl-2 but spares Mcl-1, and omacetaxine reduces Mcl-1 without affecting Bcl-2 expression, we hypothesized that their combination would target the two parallel arms of apoptosis control and kill the AML cells synergistically. Indeed, omacetaxine reduced Mcl-1 in the OCI-AML3 cells, leading to loss of mitochondrial membrane potential and apoptosis. ABT-199 blocked Bcl-2 function and also induced the intrinsic pathway of apoptosis. Their combination induced greater mitochondrial damage and apoptosis than either drug alone. The median effect analysis showed that they potentiate each other and exhibited strong synergy. Taken together, these results demonstrated that omacetaxine is active in AML cells alone and in mechanism based combinations. These actions provide rationale that warrants investigation in the clinic. Disclosures: No relevant conflicts of interest to declare.
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Seipel, Katja, Karin Schmitter, Ulrike Bacher, and Thomas Pabst. "Rationale for a Combination Therapy Consisting of MCL1- and MEK-Inhibitors in Acute Myeloid Leukemia." Cancers 11, no. 11 (November 12, 2019): 1779. http://dx.doi.org/10.3390/cancers11111779.
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Amplification and overexpression of the myeloid cell leukemia differentiation protein MCL1 and the murine double minute protein MDM2 have been reported in various human tumors as well as hematological malignancies including acute myeloid leukemia (AML). While MCL1 is an anti-apoptotic member of the BCL-2 family proteins, MDM2 is an important cellular inhibitor of the p53 tumor suppressor. The key oncogene in AML is the FLT3 growth factor receptor gene. FLT3 signaling pathways including the MAPK cascade (RAS-RAF-MEK-ERK) are highly active in AML cells, leading to induced protein translation and cell proliferation as well as reduced apoptosis. Consequently, combined administration of MCL1-, MDM2-, and MEK-inhibitors may present a promising anti-leukemic treatment strategy. Here, we assessed the MCL1-antagonist S63845, the MDM2-inhibitor HDM201, and the MEK1/2-inhibitor trametinib as single agents and in combination in a variety of AML cell lines and mononuclear cells isolated from patients with hematological malignancies centered on myeloid leukemia, some lymphatic leukemia, as well as some lymphomas, for their ability to induce apoptosis and cell death. We observed a considerably varying anti-leukemic efficacy of the MCL1-inhibitor S63845 and the MEK1/2-inhibitor trametinib. Hematological cells with susceptibility to the single compounds as well as to the combined treatment were defined by elevated MCL1- and MEK-protein levels, independent of the mutational status of FLT3 and TP53. Our data indicate that hematological cells with elevated MCL1- and MEK-protein levels are most sensitive to the combined treatment with S63845 and trametinib. MCL1- and MEK1/2-protein expression may be valid biomarkers for treatment response to S63845 and trametinib, respectively.
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Zeng, Zhihong, Ismael Samudio, Michael Andreeff, and Marina Konopleva. "Synergistic Induction of Apoptosis by Simultaneous Disruption of the Bcl-2 and mTOR/Akt Pathways in Acute Myeloid Leukemia." Blood 110, no. 11 (November 16, 2007): 1588. http://dx.doi.org/10.1182/blood.v110.11.1588.1588.
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Abstract Activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway provides survival signals for leukemic cells and blockade of this pathway may facilitate cell death. Akt/mTOR activation is a frequent event in AML that translates into significantly shorter survival of AML patients (S.M. Kornblau, ASH 2007). Bcl-2 family proteins are key regulators of apoptosis that are known to promote tumorigenesis and chemoresistance. We have recently reported that ABT-737, a small molecule BH3 mimetic, effectively kills AML progenitor cells via the disruption of Bcl-2:Bax, but its activity is largely diminished in cells overexpressing Mcl-1 (M. Konopleva, Cancer Cell 2006). We have now investigated anti-leukemia efficacy of concomitant blockade of mTOR/Akt, known to regulate Mcl-1 levels, and of Bcl-2 signaling. Combined use of rapamycin derivative temsirolimus and ABT-737 induced striking apoptotic responses in AML cell lines OCI-AML3 and MOLM13 leukemic cells. Mechanistically, temsirolimus downregulated expression of the anti-apoptotic protein Mcl-1 and induced expression levels of the proapoptotic BH3-only protein Noxa which specifically neutralizes Mcl-1. These effects were seen upon prolonged temsirolimus treatment that inhibited mTORC2 complex (Zeng, Blood 2007) and downregulated Akt phosphorylation. In primary AML samples co-cultured with bone marrow-derived stromal cells, ABT-737 at 25nM induced apoptotic cell death in CD34+ AML progenitor cells from 13 of the 16 samples tested. Temsirolimus/ABT-737 combination markedly enhanced apoptosis induction in 8/9 primary samples that were sensitive to temsirolimus alone (specific apoptosis, temsirolimus 15±5%; ABT-737, 28±5.9%; temsirolimus+ABT, 45±5.9%, p<0.001) and in 3/7 samples resistant to temsirolimus (p=0.7). Further, combined blockade of mTOR/AKT and Bcl-2 pathway effectively induced apoptosis in 3 AML samples resistant to ABT-737 alone. Taken together, these results indicate that temsirolimus can directly alter the Bcl-2 apoptotic rheostat via induction of Noxa and decreased Mcl-1 expression sensitizing leukemia cells to apoptosis induced by BH3 mimetics. The combined use of agents interfering with AKT/mTOR and Bcl-2 pathways may be a highly effective anti-leukemia strategy that induces apoptosis in AML progenitor cells in the context of bone marrow microenvironment.
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Palath, Varghese, Rohini Vekhande, Andreia Lee, Jason Williams, Ling Zhang, Alan F. List, Andrew Boyd, et al. "A Recombinant Human Antibody to EphA3 with Pro-Apoptotic and Enhanced ADCC Activity Shows Selective Cytotoxicity against Myeloid Leukemia Cells and CD123-Positive Leukemic Stem Cells." Blood 114, no. 22 (November 20, 2009): 1728. http://dx.doi.org/10.1182/blood.v114.22.1728.1728.
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Abstract Abstract 1728 Poster Board I-754 Members of the Eph family of receptor tyrosine kinases play important roles in embryonic development but have restricted tissue distribution and activity in adult tissues. The EphA3 receptor is an oncofetal antigen expressed at high levels on the surface of several solid tumor types and certain leukemias. KaloBios is in pre-clinical development with KB004, a high-affinity recombinant human antibody, derived from a monoclonal anti-EphA3 antibody by Antibody HumaneeringTM Technology. KB004 binds EphA3 and stimulates apoptosis in primary cells from myeloid leukemia patients. The cell-surface expression of EphA3 was analyzed by flow cytometry on primary cells from chronic myeloid leukemia (CML) [n=10], acute myeloid leukemia (AML) of various sub-types [n=29], and myelodysplastic syndromes (MDS) [n=7]. EphA3 surface expression was detected in at least 50% of patient samples from each of the diseases analyzed. CD123-positive leukemia stem cells (CD34+ CD38- CD123+) also displayed surface expression of EphA3 whereas normal bone marrow CD34+ stem/ progenitor cells lacked detectable EphA3. KB004 was shown to stimulate apoptosis in EphA3+ primary leukemia cells, including CD123+ leukemic stem cells with no activity in EphA3-negative specimens, including normal CD34+ bone marrow cells. Cross-linking of the antibody was not required for induction of apoptosis. KB004 also inhibited myeloid leukemia colony formation (CFU-L) from primary AML samples in methylcellulose colony assays without affecting normal hematopoietic colony formation. In addition to its direct pro-apoptotic effect, KB004 induced potent antibody-dependent cellular cytotoxicity (ADCC) activity against EphA3-positive cells, mediated by CD16-expressing effector cells. CD16-dependent ADCC activity was further enhanced by expression of the antibody in CHO cells that lack a1,6 fucosyl transferase, generating afucosylated antibody with higher affinity for CD16a. The data support the development of an anti-EphA3 antibody for the treatment of hematologic malignancies in addition to solid tumors. In particular, the selective activity against leukemic stem cells supports a novel strategy for therapeutic targeting of leukemia-initiating cells that merits clinical investigation. Disclosures No relevant conflicts of interest to declare.
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Otevřelová, Petra, and Barbora Brodská. "Chemotherapy-Induced Survivin Regulation in Acute Myeloid Leukemia Cells." Applied Sciences 11, no. 1 (January 5, 2021): 460. http://dx.doi.org/10.3390/app11010460.
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Survivin is a 16.5 kDa protein highly expressed in centrosomes, where it controls proper sister chromatid separation. In addition to its function in mitosis, survivin is also involved in apoptosis. Overexpression of survivin in many cancer types makes it a suitable target for cancer therapy. Western blotting and confocal microscopy were used to characterize the effect of chemotherapy on acute myeloid leukemia (AML) cells. We found enhanced survivin expression in a panel of AML cell lines treated with cytarabine (Ara-C), which is part of a first-line induction regimen for AML therapy. Simultaneously, Ara-C caused growth arrest and depletion of the mitotic cell fraction. Subsequently, the effect of a second component of standard therapy protocol, idarubicin, and of a known survivin inhibitor, YM-155, on cell viability and survivin expression and localization in AML cells was investigated. Idarubicin reversed Ara-C-induced survivin upregulation in the majority of AML cell lines. YM-155 caused survivin deregulation together with a viability decrease in cells resistant to idarubicin treatment, suggesting that YM-155 might be efficient in a specific subset of AML patients. Expression levels of other apoptosis-related proteins, in particular X-linked inhibitor of apoptosis (XIAP), Mcl-1, and p53, and of the cell-cycle inhibitor p21 considerably changed in almost all cases, confirming the off-target effects of YM-155.
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Xagorari, Angeliki, Sarantis Tsetsakos, Zoi Katana, Konstantinos Krikonis, Anastasia Kouvatsi, Katerina Chlichlia, Achilles Anagnostopoulos, and Damianos Sotiropoulos. "CD34+ Derived Microparticles Regulate Apoptosis in Normal and Acute Myeloid Leukemia Cells." Blood 132, Supplement 1 (November 29, 2018): 5090. http://dx.doi.org/10.1182/blood-2018-99-114425.
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Abstract Introduction Microparticles (MPs) are small vesicles 100nm-1μm derived from the apoptotic or stimulated cells. The mechanism of their production is distinctive from exosomes or apoptotic bodies. MPs have been detected in the blood in many pathological conditions associated mainly with endothelial injury, thrombosis and inflammation. Our previous study showed that MPs originated also from CD34+ cells of umbilical cord blood, which is an alternative source for hemopoeitic stem cell transplantation. MPs considered as markers of cell activation, as well as apoptosis. Apoptosis is a complex interaction network regulated either through death receptor like FAS or through the internal pathway of Bcl2, Bax. The two pathways activate the executor of cell death program, caspases. The aim of this study is to elucidate the role of MPs in apoptosis of hemopoietic cells. Methods Umbilical cord blood units (UCB) were collected after informed consent. The units that were used in this study, were rejected as not appropriate for transplantation due to low volume. The HL60 promyelocytic leukemia cell line was cultured in RPMI (Life Technologies) supplemented with 10% fetal calf serum (FCS) and 1% penicillin-strepromycin. CD34+ MPs were isolated from the plasma of UCBs after centrifugation and magnetic bead MACS purification (Miltenyi Biotec). The number of CD34+ MPs was estimated by flow cytometry using CD34-PE and Annexin V-FITC Abs. Mononuclear cells (MNC) were collected after density gradient centrifugation on lymphoprep (Fresenius) and were cultured for 3 and 6 days in the presence of CD34+ MPs. Viability assays were performed using 7-AAD in flow cytometry. In another set of experiments different numbers of CD34+ MPs were used in MNC cultures. RNA was extracted from MNC using Qiagen RNA extraction kit and reverse transcribed into cDNA using Superscript II reverse transcriptase (Invitrogen) with random primers (Promega). RT-PCR was performed using Platinum Pfx polymerase (Invitrogen). The primers for FAS, BCL2, BAX, caspase 3, survivin and GAPDH genes were used. The PCR products were analysed in an agarose gel electrophoresis. Results Cell viability increased in UCB derived MNC (UCB-MNC) incubated with CD34+ MPs (800 /ml) after 3 day vs. 6 days of culture. The UCB-MNC viability was higher using 800/ml CD34+ MPs vs. 400/ml. In contrast, CD34+ MPs (800 /ml vs. 400/ml) did not affect the viability in one day MNC culture. Purified CD34+ MPs were applied to UCB-MNC cultures and by RT-PCR was shown increased expression of BCL2 gene as well as FAS and caspase-3 genes. The promyelocytc cell line HL60 has been used in order to analyze the effect of CD34+ MPs in leukemic cells. The expression of Bcl2 was decreased in HL60 cells co-incubated with CD34+ MPs. This result shows an opposite effect of CD34+ MPs in the apoptotic gene Bcl2 for the HL60 cells indicating that there are different mechanisms of MP function in various cell types. Conclusions In this study we have identified and monitored the time- and dose-dependent effect of CD34-derived microparticles in the viability of UCB mononuclear cells. Additionally, CD34+ MPs function is accosiated with the high expression of the pro- and anti-apoptotic Bcl2 and apoptotic FAS. In contrast CD34+ MPs decreases the expression of Bcl2 in the promyelocytic leukemia cell line HL60. Therefore the stem cell derived microparticles might serve as a potential regulator of apoptosis in normal and malignant hematopoietic cells. Disclosures No relevant conflicts of interest to declare.
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Allouche, Michèle, Rachida Sihem Charrad, Ali Bettaieb, Catherine Greenland, Cécile Grignon, and Florence Smadja-Joffe. "Ligation of the CD44 adhesion molecule inhibits drug-induced apoptosis in human myeloid leukemia cells." Blood 96, no. 3 (August 1, 2000): 1187–90. http://dx.doi.org/10.1182/blood.v96.3.1187.
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Abstract Adhesion molecules can improve hematopoietic cell survival; however, their role in leukemic cell resistance to drug-induced apoptosis is poorly documented. The CD44 adhesion molecule is strongly expressed on acute myeloid leukemia (AML) blasts. Using 2 myeloid cell lines, HL60 and NB4, evidence is presented that prior incubation with the CD44-specific monoclonal antibody (mAb) A3D8, reported to induce differentiation of AML blasts, significantly decreases apoptosis induced by 3 drugs used in AML chemotherapy: daunorubicin (DNR), mitoxantrone, and etoposide. In addition, in HL60 cells, CD44 ligation with A3D8 mAb fully abrogates the DNR-triggered generation of ceramide, a lipid second messenger involved in the DNR apoptotic signaling pathway. Moreover, results show that the A3D8 mAb and Bcl-2 additively inhibit DNR-induced apoptosis in HL60 cells overexpressing Bcl-2. These results suggest that, to eradicate AML blasts, the differentiation-inducing anti-CD44 mAb A3D8 should not be administered prior to apoptosis-inducing drugs.
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Allouche, Michèle, Rachida Sihem Charrad, Ali Bettaieb, Catherine Greenland, Cécile Grignon, and Florence Smadja-Joffe. "Ligation of the CD44 adhesion molecule inhibits drug-induced apoptosis in human myeloid leukemia cells." Blood 96, no. 3 (August 1, 2000): 1187–90. http://dx.doi.org/10.1182/blood.v96.3.1187.015k01_1187_1190.
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Adhesion molecules can improve hematopoietic cell survival; however, their role in leukemic cell resistance to drug-induced apoptosis is poorly documented. The CD44 adhesion molecule is strongly expressed on acute myeloid leukemia (AML) blasts. Using 2 myeloid cell lines, HL60 and NB4, evidence is presented that prior incubation with the CD44-specific monoclonal antibody (mAb) A3D8, reported to induce differentiation of AML blasts, significantly decreases apoptosis induced by 3 drugs used in AML chemotherapy: daunorubicin (DNR), mitoxantrone, and etoposide. In addition, in HL60 cells, CD44 ligation with A3D8 mAb fully abrogates the DNR-triggered generation of ceramide, a lipid second messenger involved in the DNR apoptotic signaling pathway. Moreover, results show that the A3D8 mAb and Bcl-2 additively inhibit DNR-induced apoptosis in HL60 cells overexpressing Bcl-2. These results suggest that, to eradicate AML blasts, the differentiation-inducing anti-CD44 mAb A3D8 should not be administered prior to apoptosis-inducing drugs.
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Kim, Hee Nam, Li Yu, Nan young Kim, Il-Kwon Lee, Yeo-Kyeoung Kim, Deok-Hwan Yang, Je-Jung Lee, et al. "Polymorphisms in Myeloid Cell Leukemia-1 and the Risk for Acute Myeloid Leukemia." Blood 112, no. 11 (November 16, 2008): 3977. http://dx.doi.org/10.1182/blood.v112.11.3977.3977.
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Abstract The essential pathogenic mechanism in acute myeloid leukemia (AML) is a heterogeneous group of malignant diseases arising as the result of progressive genetic damage occurring in hemopoietic progenitor cells. Mcl-1 (myeloid cell leukemia-1), an antiapoptotic protein of the Bcl-2 family, is located on chromosome 1 and has three exons and two introns. Overexpression of Mcl-1 delays apoptosis induced by cytotoxic agents, c-myc overexpression, and growth factor withdrawal in hematopoietuc cells. To evaluate the association between genetic variants of Mcl-1 gene and risk of AML, we genotyped two polymorphisms in promoter of Mcl-1[rs3738484; −324 C>A and rs3831987; −284 insertion(6bp or18bp)/deletion]. A case-control study of 728 controls and 660 cases was conducted in Chonnam National University Hwasun Hospital, Korea. The Mcl −324 CA and combined CA/AA genotype was significantly associated with a decreased risk for AML [odds ratio (OR) CA = 0.75; 95% confidence interval (CI) = 0.60–0.95; ORCA/AA = 0.76; 95% CI = 0.61–0.96]. There was no association with the Mcl -284 insertion/deletion and AML. The haplotype A-ins18bp is significantly associated with the risk of AML. Using subjects with the haplotype A- del, the OR of haplotype A-ins18bp is 5.87 (95% CI 1.7–20.06 p= 0.006). Our results suggest that antiapoptotic protein, Mcl-1 polymorphism may influence susceptibility to AML.
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Pikman, Yana, Alexandre Puissant, Gabriela Alexe, Andrew Furman, Stacey Frumm, Linda Ross, Liying Chen, et al. "Targeting MTHFD2 in Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 443. http://dx.doi.org/10.1182/blood.v126.23.443.443.
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Abstract Alterations in differentiation pathways contribute to the development of acute myeloid leukemia (AML). Differentiation therapy with all-trans retinoic acid (ATRA) has dramatically altered the treatment of acute promyelocytic leukemia, transforming it from a nearly fatal disease to a curable one. We set out to identify cellular pathways that contribute to AML differentiation, with the goal of identifying new therapeutic targets. We analyzed gene expression data from AML cell lines treated with phorbol 12-myristate 13-acetate (PMA), ATRA, Vitamin D, the BET inhibitor JQ1 and the DOT1L inhibitor EPZ00477, treatments known to induce AML differentiation and impair growth. Folate-mediated one-carbon metabolism was one of only three metabolic pathways altered by these compounds, with expression of MTHFD2 consistently downregulated with each compound. MTHFD2 is an NAD-dependent, bi-functional mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase. It is differentially expressed in embryonic and transformed tissues and is upregulated in myeloid progenitors. MTHFD2 is the most differentially expressed metabolic enzyme in cancer cells versus normal cells, including normal proliferating cells. We thus investigated the role of MTHFD2 in myeloid malignancy. First, we demonstrated using ChIP-qPCR, MYC knockdown and MYC inhibition with a BET inhibitor, that MYC directly regulates MTHFD2 expression in AML. Knockdown of MTHFD2 with two shRNAs confirmed to have on-target activity, induced myeloid differentiation in AML cell lines, as measured by Cd11b expression, morphologic changes and induction of a previously validated AML differentiation gene expression signature. MTHFD2 knockdown decreased cell growth in AML cell lines, as well as decreased colony formation in methylcellulose in both AML cell lines and primary patient blasts. AML cells transduced with these two MTHFD2-directed shRNAs demonstrated attenuated growth in an orthotopic mouse model of AML. Furthermore, three MTHFD2-directed shRNAs prolonged survival in an MLL-AF9 mouse leukemia model. Additionally, using a doxycycline inducible shRNA system, we demonstrated that two miR30-shRNAs directed against MTHFD2 decreased AML burden in mice with established disease and prolonged survival. To identify biomarkers of response to MTHFD2 suppression, we used single sample Gene Set Enrichment Analysis (ssGSEA) to identify primary patient AML samples enriched for gene expression signatures of folate-mediated one-carbon metabolism and MTHFD2. We found in both independent data sets that the cluster of patients enriched for expression of the one-carbon folate pathway gene signatures was also enriched for patients with FLT3-ITD mutations, a subset of AML with a particularly poor prognosis. In addition, in an shRNA screen targeting 11,194 genes and performed in 216 cancer cell lines, including 17 AML lines, FLT3-ITD was a biomarker of response to MTHFD2 knockdown. We next validated that while MTHFD2 suppression induced measureable differentiation in all six AML cell lines examined, it induced the most robust induction of apoptosis in FLT3-ITD mutant AML. The mitochondrial one-carbon folate pathway is thought to contribute to cellular oxidative balance by providing reducing power in the form of NAD(P)H, and suppression of MTHFD2 was previously shown to increase ROS levels. Indeed, suppression of MTHFD2 led to a marked increase in ROS in the FLT3-ITD positive AML cell lines in which apoptosis was induced. In summary, a decrement in MTHFD2 expression was found at the center of multiple AML perturbations that impair AML growth and induce differentiation. Our data support MTHFD2 as an AML dependency and FLT3-ITD as a potential biomarker of response. We thus provide critical preclinical evidence for targeting of MTHFD2 as a therapeutic strategy in AML. Disclosures Stone: Celgene: Consultancy; Merck: Consultancy. DeAngelo:Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Agios: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy. Stegmaier:Novartis Pharmaceuticals: Consultancy.
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Yeh, Su-Peng, Yu-Chien Chang, Wen-Jyi Lo, Min-Lih Huang, Yang-Sheng Yang, Pei Ching Hsiao, and Dian-Kun Li. "Deferasirox Inhibit Doxorubicin-Induced Reactive Oxygen Species Generation in Both Acute Myeloid Leukemia and Normal Heart Cell While Maintain the Cytotoxicity of Doxorubicin Only on Acute Myeloid Leukemia." Blood 120, no. 21 (November 16, 2012): 3620. http://dx.doi.org/10.1182/blood.v120.21.3620.3620.
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Abstract Abstract 3620 Background: Deferasirox (DFX) was recently found to have anti-leukemia effect both in vitro and in vivo. DFX can also potently inhibit the generation of intracellular reactive oxygen species (ROS). On the other hand, the generation of ROS by Doxorubicin (DOX) is critical for the cytotoxicity on both leukemia and normal heart cells. It is not known whether combining DFX and DOX will have synergistic or antagonizing effect on leukemic cells. Similarly, it is also unknown whether adding DFX to DOX will have protective effect on normal heart cell. Method: Cells of human acute myeloid leukemia (AML) cell line THP1, mice AML cell line WEHI3, and rat normal heart cell line H9C2 were treated with Doxorubicin 5microM for various duration in the presence of absence of DFX pretreatment (100microM for 10 minutes). Intracellular ROS generation was measured by the detection of 2,7-dichlorodihydrofluorescein (DCF) fluorescence intensity using flow cytometry. Apoptosis was determined by Annexin V-Propidium Iodide staining using flow cytometry. Cytotoxicity was determined by Trypan blue exclusion assay. Results: Although intracellular ROS was reduced, DFX alone induced apoptosis of THP1 (from 3% to 18%) and WEHI3 (from 31% to 49%) AML cells. DOX-induced ROS production was also significantly reduced when THP1, WEHI3, and H9C2 cells were pretreated with DFX (Figure 1a, 1b, 1c respectively). However, the DOX-induced apoptosis of THP1 and WEHI3 AML cells were not antagonized by DFX (Figure 2a). 24 hours after exposure to this physiological dose DOX, all the WEHI3 cells died in both DFX treated or untreated group (figure 2b). More importantly, DFX-pretreated H9C2 heart cells had fewer cell death (3.7%) after exposure to DOX (5microM for 24 hours) compared to non-DFX pretreated cells (8.5%). Conclusions: DFX alone induced apoptosis in two different AML cell lines. DFX also markedly reduced the ROS generation due to DOX treatment. However, DFX did not negatively influence the pro-apoptotic and cytotoxic effect of DOX on these AML cell lines. Interestingly, DFX also markedly reduced the DOX-induced ROS generation and DOX-induced cell death in normal rat heart cell, which might have protective effect on DOX-related cardiomyopathy. We are now using Balb/c-WEHI3 AML mice model to test whether DFX can protect cardiomyocytes from DOX-related damage while maintain the cytotoxic effect of DOX on AML cells. Disclosures: No relevant conflicts of interest to declare.
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Banker, Deborah E., Mark Groudine, Tom Norwood, and Frederick R. Appelbaum. "Measurement of Spontaneous and Therapeutic Agent-Induced Apoptosis With BCL-2 Protein Expression in Acute Myeloid Leukemia." Blood 89, no. 1 (January 1, 1997): 243–55. http://dx.doi.org/10.1182/blood.v89.1.243.
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Abstract We have designed in vitro assays to investigate the possible association between apoptosis and chemotherapeutic sensitivity in acute myeloid leukemias (AMLs). Consistent low levels of spontaneous apoptosis were observed in myeloid cells from normal bone marrow samples, while untreated cells collected from 56 de novo AML patients showed variable apoptosis. Control myeloid cells showed increased apoptosis after in vitro treatments with daunomycin (DNR), cytosine arabinoside (ARA-C), or gamma irradiation (RAD). Most AML samples showed less treatment-associated apoptosis, suggesting that apoptosis responses to therapeutic agents may be frequently attenuated in AML. Certain cytogenetic abnormalities common in AML may affect apoptosis, as acute promyelocytic leukemia (APL) samples with t(15; 17) karyotypes showed consistently low levels of spontaneous and treatment-associated apoptosis. Apoptosis assays may provide unique functional subtyping of AMLs, as other common cytogenetic subsets showed variable apoptosis. Altered function of two well-characterized regulators of apoptosis, BCL-2 and p53, was not entirely responsible for this variability. A genomic p53 mutation was found in only one AML sample. All samples that demonstrated the highest BCL-2–positive cell fractions showed low apoptosis, but reduced apoptosis was seen in both the presence and absence of BCL-2 overexpression. Finally, data from matched diagnosis and relapse sample pairs suggest that neither further reduced apoptosis nor additional BCL-2 overexpression is necessarily associated with disease progression.
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Banker, Deborah E., Mark Groudine, Tom Norwood, and Frederick R. Appelbaum. "Measurement of Spontaneous and Therapeutic Agent-Induced Apoptosis With BCL-2 Protein Expression in Acute Myeloid Leukemia." Blood 89, no. 1 (January 1, 1997): 243–55. http://dx.doi.org/10.1182/blood.v89.1.243.243_243_255.
Full textAbstract:
We have designed in vitro assays to investigate the possible association between apoptosis and chemotherapeutic sensitivity in acute myeloid leukemias (AMLs). Consistent low levels of spontaneous apoptosis were observed in myeloid cells from normal bone marrow samples, while untreated cells collected from 56 de novo AML patients showed variable apoptosis. Control myeloid cells showed increased apoptosis after in vitro treatments with daunomycin (DNR), cytosine arabinoside (ARA-C), or gamma irradiation (RAD). Most AML samples showed less treatment-associated apoptosis, suggesting that apoptosis responses to therapeutic agents may be frequently attenuated in AML. Certain cytogenetic abnormalities common in AML may affect apoptosis, as acute promyelocytic leukemia (APL) samples with t(15; 17) karyotypes showed consistently low levels of spontaneous and treatment-associated apoptosis. Apoptosis assays may provide unique functional subtyping of AMLs, as other common cytogenetic subsets showed variable apoptosis. Altered function of two well-characterized regulators of apoptosis, BCL-2 and p53, was not entirely responsible for this variability. A genomic p53 mutation was found in only one AML sample. All samples that demonstrated the highest BCL-2–positive cell fractions showed low apoptosis, but reduced apoptosis was seen in both the presence and absence of BCL-2 overexpression. Finally, data from matched diagnosis and relapse sample pairs suggest that neither further reduced apoptosis nor additional BCL-2 overexpression is necessarily associated with disease progression.
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Ramaswamy, Kavitha, Lauren Forbes, Fiona C. Brown, Richard Koche, Tatyana Gindin, Gerard Minuesa, Michael G. Kharas, et al. "Peptidomimetic Blockade of MYB in Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 3945. http://dx.doi.org/10.1182/blood.v128.22.3945.3945.
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Abstract Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for its blockade are generally lacking, in large part due to the pharmacologic challenges of drugging transcription factors. MYB-driven gene trans-activation with CREB-binding protein (CBP) is required for the initiation and maintenance of a variety of acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a prototypical peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP complex at μM concentrations and rapidly accumulates in the nuclei of AML cells. We found that treatment of AML cells with MYBMIM, but not with its inactive near-isosteric analogue TG3, led to the displacement and dissociation of MYB:CBP complex in cells, causing rapid downregulation of MYB-dependent gene expression including MYC and BCL2 oncogenes. This was associated with obliteration of H3K27Ac-driven oncogenic enhancers induced by CBP and enriched for MYB binding sites (Figure 1A; p=1e-118). Both human MLL-rearranged and non-rearranged AML cells, but not normal CD34+ umbilical cord blood progenitor cells, underwent sustained mitochondrial apoptosis in response to MYBMIM treatment, an effect that could be partially blocked by ectopic expression of BCL2. We observed that MYBMIM treatment (50 mg/kg/day) impeded leukemia progression and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells (Figure 1B; p=3.8e-3). These findings emphasize the exquisite dependence of human AML on MYB:CBP transcriptional dysregulation, and establish a pharmacologic approach for its therapeutic blockade. Figure MYBMIM blocks oncogenic gene expression (A) and impedes leukemogenesis in vivo(B). Figure. MYBMIM blocks oncogenic gene expression (A) and impedes leukemogenesis in vivo(B). Disclosures Armstrong: Epizyme, Inc: Consultancy; Vitae Pharmaceuticals: Consultancy; Imago Biosciences: Consultancy; Janssen Pharmaceutical: Consultancy.