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Journal articles on the topic 'Myeloid Cell Leukemia 1 (MCL1)'

Author: Grafiati

Published: 7 September 2021

Last updated: 29 July 2025

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1

Luo, Hui, Jennifer A. Cain, AnnaLynn Molitoris, Joseph Opferman, and Michael H. Tomasson. "Myc Induces Acute Myeloid Leukemia by Conferring Self-Renewal Activity to Committed Myeloid Progenitor Cells That Resist Apoptosis Via Endogenous Mcl-1." Blood 110, no. 11 (2007): 2634. http://dx.doi.org/10.1182/blood.v110.11.2634.2634.

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Abstract Ectopic expression of Myc in most primary cell types induces apoptosis, and cancer development typically requires additional, anti-apoptotic mutations. We reported previously that ectopic expression of Myc in unfractionated murine bone marrow cells induced rapid onset acute myeloid leukemia (AML) without detectable anti-apoptotic mutations. We hypothesized that AML developed in our model because a subset of normal primary bone marrow cells were inherently resistant to Myc-induced apoptosis. Consistent with this model, seven days of Myc activation in the bone marrow of mice caused the

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Sevin, Margaux, Franck Debeurme, Lucie Laplane, et al. "Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML." Blood 137, no. 24 (2021): 3390–402. http://dx.doi.org/10.1182/blood.2020008729.

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Abstract Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK)

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Acton, Alexus, and William J. Placzek. "Myeloid Cell Leukemia 1 Small Molecule Inhibitor S63845 Synergizes with Cisplatin in Triple-Negative Breast Cancer." Cancers 15, no. 18 (2023): 4481. http://dx.doi.org/10.3390/cancers15184481.

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Triple-negative breast cancer (TNBC) is an aggressive cancer that lacks specific molecular targets that are often used for therapy. The refractory rate of TNBC to broad-spectrum chemotherapy remains high; however, the combination of newly developed treatments with the current standard of care has delivered promising anti-tumor effects. One mechanism employed by TNBC to avoid cell death is the increased expression of the anti-apoptotic protein, myeloid cell leukemia 1 (MCL1). Multiple studies have demonstrated that increased MCL1 expression enables resistance to platinum-based chemotherapy. In

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Mukai, Risa, and Takayuki Ohshima. "Enhanced Stabilization of MCL1 by the Human T-Cell Leukemia Virus Type 1 bZIP Factor Is Modulated by Blocking the Recruitment of Cullin 1 to the SCF Complex." Molecular and Cellular Biology 36, no. 24 (2016): 3075–85. http://dx.doi.org/10.1128/mcb.00450-16.

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Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is the etiological agent of adult T-cell leukemia (ATL). The HTLV-1 basic leucine zipper factor (HBZ), which is encoded by the minus strand of the provirus, is constitutively expressed in all ATL patient cells and likely contributes to the development and maintenance of ATL. Furthermore, the overexpression of the myeloid cell leukemia 1 (MCL1) protein is frequently observed in hematological cancers as well as several other types of cancers. Here, we found that the expression of HBZ in cells stabilized MCL1 protein expr

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Moujalled, Donia M., Giovanna Pomilio, Thomas Morley, et al. "CD74 Antibody Conjugated to an MCL1 Inhibitor (S227928) Combines Synergistically with Venetoclax to Enhance Killing of Acute Myeloid Leukemia." Blood 144, Supplement 1 (2024): 4136. https://doi.org/10.1182/blood-2024-202691.

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Background: BCL2 pro-survival proteins (BCL2, MCL1, BCL-XL) function as key regulators of oncogenic survival. BH3-mimetic drugs bind to pro-survival proteins (e.g. venetoclax to BCL2), enhancing BH3-only proteins to induce BAX/BAK dependent apoptosis. MCL1 is overexpressed in acute myeloid leukemia (AML) and increased expression has been observed in leukemias resistant to venetoclax-based therapy. Co-targeting BCL2 and MCL1 with selective BH3-mimetics has synergistic activity in diverse AML cases, including TP53-mutated disease (Thijssen, Blood, 2021). Clinical development of MCL1 inhibitors h

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Powell, Jason A., Alexander C. Lewis, Wenying Zhu, et al. "Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia." Blood 129, no. 6 (2017): 771–82. http://dx.doi.org/10.1182/blood-2016-06-720433.

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Key Points Inhibition of SPHK1 in human AML cells induces MCL1 degradation and caspase-dependent cell death. SPHK1 inhibitors reduce leukemic burden and prolong survival in orthotopic patient-derived xenografts of AML.

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Garzon, Ramiro, Flavia Pichiorri, Guido Marcucci, Steve Kornblau, Michael Andreeff, and Carlo Croce. "MiRNA-29b Targets MCL-1 and Is Down-Regulated in Chemotherapy-Resistant Acute Myeloid Leukemia (AML)." Blood 110, no. 11 (2007): 717. http://dx.doi.org/10.1182/blood.v110.11.717.717.

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Abstract AML is a heterogeneous disorder that includes several differently biologic entities. Patients with intermediate and poor-risk cytogenetics represent the majority of AML and chemotherapy-based regimens fail to cure most of these patients that are either resistant to or relapse shortly after treatment. Therefore, it is crucial to understand the biology of chemotherapy resistance in AML. Here, we proposed to investigate the relation between chemoresistance and miRNA expression in AML. First, using a miRNA microarray platform, we analyzed the miRNA profiles in pretreatment samples from a

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Golla, Upendarrao, Satyam Patel, Jeremy Hengst, et al. "Abstract 7227: Isatin analogs potentiate the cytotoxicity of venetoclax in acute myeloid leukemia cells." Cancer Research 84, no. 6_Supplement (2024): 7227. http://dx.doi.org/10.1158/1538-7445.am2024-7227.

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Abstract Acute Myeloid Leukemia (AML) is a rare but common hematological malignancy in children and adults. AML is a highly heterogeneous disease caused by the acquisition of several mutations affecting multiple cellular processes, thus requiring concomitant targeting of key survival nodes to treat effectively. As current first-line therapies for AML suffer with poor outcomes, drug resistance, and high relapse rates, there is an immediate need for new combinatorial therapies that are both safe and effective. Venetoclax (VEN), a selective inhibitor of antiapoptotic protein B-cell lymphoma-2 (BC

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Lazzari, Elisa, Leslie A. Crews, Christina Wu, et al. "Targeting Cancer Stem Cell Survival in Plasma Cell Leukemia with a Pan-BCL2 Inhibitor." Blood 126, no. 23 (2015): 5351. http://dx.doi.org/10.1182/blood.v126.23.5351.5351.

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Abstract INTRODUCTION Representing ten percent of all hematologic malignancies, multiple myeloma (MM) is typified by clonal plasma cell proliferation in the bone marrow (BM) and may progress to a therapy-resistant stage characterized by circulating malignant plasma cells, which is termed plasma cell leukemia, (PCL). Notably, copy number amplification involving the myeloid cell leukemia (MCL)-1 locus, and translocations at the BCL2 locus have been described in high-risk MM. Moreover, BCL2 family members, including both MCL1 and BCL2, are highly expressed in relapsed MM. Finally, downregulation

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Chakraborty, Samarpana, Claudia Morganti, Joyoti Dey, et al. "A STAT3 Degrader Demonstrates Pre-Clinical Efficacy in Venetoclax Resistant Acute Myeloid Leukemia." Blood 142, Supplement 1 (2023): 2787. http://dx.doi.org/10.1182/blood-2023-186947.

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Introduction: Acute Myeloid leukemia (AML) is an aggressive hematological malignancy resulting from the transformation of immature myeloid progenitor cells followed by an uncontrolled clonal proliferation and accumulation of the transformed cells. AML is the most common myeloid malignancy in the elderly [1]. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein. Ven is FDA approved in combination with hypomethylating agents (HMA's) or low dose cytarabine for the treatment of de-novo AML in patients &gt; 75 years or those ineligible for standard induction therapies. D

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Emhoff, Kylin A., Jesse A. Coker, and Jan J. Melenhorst. "Abstract 6797: Mechanisms of nuclear MCL1 mediated chemoresistance." Cancer Research 85, no. 8_Supplement_1 (2025): 6797. https://doi.org/10.1158/1538-7445.am2025-6797.

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Abstract The upregulation of anti-apoptotic BCL2 family members is a major mechanism of chemoresistance in many solid cancers. MCL1 (myeloid cell leukemia 1), an anti-apoptotic member of BCL2 family, is overexpressed in many solid tumors and associates with poor prognosis and therapeutic failure. In addition to its anti-apoptotic functions, MCL1 reportedly has non-apoptotic, nuclear functions that play a role in DNA damage response, cell cycle, and chemoresistance. However, the nuclear functions of MCL1 remain sparse and unelucidated. Our lab has investigated the nuclear interactome of MCL1 in

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Balakrishnan, Kumudha, Christine M. Stellrecht, Davide Genini, et al. "Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP." Blood 105, no. 11 (2005): 4455–62. http://dx.doi.org/10.1182/blood-2004-05-1699.

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Abstract Myeloid cell leukemia-1 (MCL-1) acts as a key survival factor for chronic lymphocytic leukemia (CLL) cells. In addition, dissipation of cellular bioenergy may impose a lethal effect on these quiescent cells. Previously, in multiple myeloma cell lines we demonstrated that halogenated adenosine (8-Cl-Ado) was phosphorylated to triphosphate (8-Cl–adenosine triphosphate [ATP]), which preferentially incorporated into mRNA and inhibited RNA synthesis by premature transcription termination. Furthermore, 8-Cl-ATP accumulation was associated with a decline in cellular bioenergy. Based on these

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Jiao, Changqing, Chen Hu, Mengya Pan, Junjie Zhou, Qingsong Liu, and Jian Ge. "Pharmacological Inhibition of METTL3 Enhances the Acute Myeloid Leukemia Cell Death Induced By Venetoclax Via the METTL3-YTHDF2-FBXW7-MCL1 Axis." Blood 144, Supplement 1 (2024): 4153. https://doi.org/10.1182/blood-2024-206666.

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Overexpression of BCL2 leads to survival of acute myeloid leukemia (AML) cells and poor prognosis. Targeting BCL2 by Venetoclax, a BH3 mimetic and selective inhibitor of BCL2, is widely utilized in clinical practice. However, the clinical utility of venetoclax is constrained by the acquired drug resistance. STM2457, an inhibitor of METTL3, has demonstrated the ability to arrest the proliferation of AML cells in pre-clinical models. Nonetheless, the combined effects of STM2457 and venetoclax in AML have yet to be investigated. To evaluate the potential synergistic interaction between venetoclax

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Vanderkerken, Karin, Kim De Veirman, Ken Maes, Eline Menu, and Elke De Bruyne. "MCL1 Inhibitors in Multiple Myeloma." Blood 134, Supplement_1 (2019): SCI—12—SCI—12. http://dx.doi.org/10.1182/blood-2019-121104.

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Apoptosis plays a key role, not only in normal homeostasis but also in protection against genomic instability. Protection against apoptosis is a hallmark of cancer and is mainly regulated by the overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-Xl or Mcl-1. This results in increased survival of the tumor cells and resistance to therapy. This presentation will focus on MCL-1 (myeloid cell leukemia 1), its expression and its role as potential target in multiple myeloma (MM). MCL1 gene regions are one the most amplified gene regions in several human cancers and Mcl-1 activity is often

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Papatzimas, James W., Evgueni Gorobets, Ranjan Maity, et al. "From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)." Journal of Medicinal Chemistry 62, no. 11 (2019): 5522–40. http://dx.doi.org/10.1021/acs.jmedchem.9b00455.

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Zhang, Di, Franklin Li, Douglas Weidner, Zakar H. Mnjoyan, and Ken Fujise. "Physical and Functional Interaction between Myeloid Cell Leukemia 1 Protein (MCL1) and Fortilin." Journal of Biological Chemistry 277, no. 40 (2002): 37430–38. http://dx.doi.org/10.1074/jbc.m207413200.

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Viant, Charlotte, Sophie Guia, Robert J. Hennessy, et al. "Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival." Journal of Experimental Medicine 214, no. 2 (2017): 491–510. http://dx.doi.org/10.1084/jem.20160869.

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Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)–induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferatin

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Bloedjes, Timon A., Guus de Wilde, Chiel Maas, et al. "AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma." Blood Advances 4, no. 17 (2020): 4151–64. http://dx.doi.org/10.1182/bloodadvances.2019001393.

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Abstract The phosphatidylinositide-3 kinases and the downstream mediator AKT drive survival and proliferation of multiple myeloma (MM) cells. AKT signaling is active in MM and has pleiotropic effects; however, the key molecular aspects of AKT dependency in MM are not fully clear. Among the various downstream AKT targets are the Forkhead box O (FOXO) transcription factors (TFs) and glycogen synthase kinase 3 (GSK3), which are negatively regulated by AKT signaling. Here we show that abrogation of AKT signaling in MM cells provokes cell death and cell cycle arrest, which crucially depends on both

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Fang, Chao, Brendan D’Souza, Christopher F. Thompson, et al. "Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1)." ACS Medicinal Chemistry Letters 5, no. 12 (2014): 1308–12. http://dx.doi.org/10.1021/ml500388q.

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20

Singaravelu, Balasubramanian, and Marimuthu. "Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1." Processes 7, no. 4 (2019): 224. http://dx.doi.org/10.3390/pr7040224.

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Myeloid cell leukemia-1 (Mcl1) is an anti–apoptotic protein that has gained considerable attention due to its overexpression activity prevents cell death. Therefore, a potential inhibitor that specifically targets Mcl1 with higher binding affinity is necessary. Recently, a series of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds was reported that targets Mcl1, but its binding mechanism remains unexplored. Here, we attempted to explore the molecular mechanism of binding to Mcl1 using advanced computational approaches: pharmacophore-based 3D-QSAR, docking, and MD simulation. The sele

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Gu, Yongzhong, Jinlai Meng, Changting Zuo, et al. "Downregulation of MicroRNA-125a in Placenta Accreta Spectrum Disorders Contributes Antiapoptosis of Implantation Site Intermediate Trophoblasts by Targeting MCL1." Reproductive Sciences 26, no. 12 (2019): 1582–89. http://dx.doi.org/10.1177/1933719119828040.

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The typical hallmark of placenta accreta spectrum (PAS) disorders is increased implantation site intermediate trophoblast (ISIT) cell numbers. However, the extent of trophoblast proliferation and apoptosis have not been found to differ from those of normal placentation. MicroRNA-125a (miR-125a) induces apoptosis in colon cancer cell by targeting myeloid cell leukemia-1 gene ( MCL1). We aimed to investigate the influence of miR-125a on ISIT cells in PAS disorders in 15 patients (self-paired trials) with placenta previa and PAS disorders. Expression of miR-125a and MCL1 were measured in villous

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Haferlach, Claudia, Wencke Walter, Alexander Höllein, et al. "Identification and Characterization of Potential Candidates for Treatment Targeting Apoptosis Pathways in Patients with Hematological Neoplasms." Blood 132, Supplement 1 (2018): 4098. http://dx.doi.org/10.1182/blood-2018-99-117927.

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Abstract Background: Resistance to apoptosis is one of the hallmarks in hematological neoplasms, most typically via dysregulation of the intrinsic mitochondrial pathway. The most important antiapoptotic/pro-survival proteins in this pathway are BCL2, BCL2L1 and MCL1. Molecules targeting each of these proteins are in various stages of preclinical and clinical development. The BCL2 inhibitor venetoclax is the first FDA approved drug in this setting and was shown to be highly effective in CLL and some B-cell lymphoma subtypes. Kumar et al. (Blood 2017) reported that in multiple myeloma response t

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Aveic, Sanja, Elena Manara, Benedetta Accordi, et al. "BAG1 Overexpression Restrains the Anti-Apoptotic BCL2, MCL1 and HSP70 Proteins in Acute Myeloid Leukemia." Blood 120, no. 21 (2012): 2492. http://dx.doi.org/10.1182/blood.v120.21.2492.2492.

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Abstract Abstract 2492 BACKGROUND: Childhood Acute Myeloid Leukemia (AML) is a heterogeneous disease characterized by recurrent genetic aberrations; impaired apoptosis of leukemia cells can also contribute to disease development. BCL2-associated AthanoGene1 (BAG1) is a multifunctional protein preferentially supporting cell survival. Its aberrant expression was demonstrated in diverse cancer types. We previously reported high expression of BAG1 protein in leukemia cell lines. We showed that leukemic cell survival was impaired after silencing BAG1. Additionally, we confirmed that, in vitro, BAG1

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Mondala, Phoebe, Inge Van Der Werf, Larisa Balaian, et al. "Deregulation of Splicing in Pediatric Acute Myeloid Stem and Progenitor Cells." Blood 138, Supplement 1 (2021): 2227. http://dx.doi.org/10.1182/blood-2021-154120.

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Abstract - Currently, the limited capacity of pediatric acute myeloid leukemia (AML) therapies to prevent recurrence has contributed to high mortality rates. While dormant self-renewing leukemia stem cells (LSCs) contribute to adult AML relapse, their role in pediatric AML therapeutic resistance has not been clearly elucidated and thus was investigated in the context of this study. Through whole transcriptome sequencing (RNA-seq) analyses of FACS-purified human hematopoietic stem cells (HSCs; CD34 +CD38 -Lineage -) and progenitor cells (HPCs; CD34 +CD38 + Lineage -) from pediatric AML (n=10) c

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Seipel, Katja, Carolyn Graber, Laura Flückiger, Ulrike Bacher, and Thomas Pabst. "Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia." International Journal of Molecular Sciences 22, no. 15 (2021): 8092. http://dx.doi.org/10.3390/ijms22158092.

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The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3-mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inh

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Wang, Yubao, Michael Begley, Qing Li, et al. "Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival." Proceedings of the National Academy of Sciences 113, no. 35 (2016): 9810–15. http://dx.doi.org/10.1073/pnas.1606862113.

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The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle. We further show that the MELK–eIF4B signaling axis regula

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Bejarano Garcia, Jose Antonio, Melanie Nufer, Maria Jose Palacios Barea, et al. "Role of Antiapoptotic Protein Mcl1 in Graft-Versus-Host Disease." Blood 144, Supplement 1 (2024): 3395. https://doi.org/10.1182/blood-2024-200823.

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Introduction Graft-versus-host disease (GvHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Induced myeloid leukemia cell differentiation protein (Mcl1) is an antiapoptotic protein and a member of the Bcl2 family protein, which regulates the intrinsic mitochondrial pathway of apoptosis. Additionally, Mcl1 is the only antiapoptotic protein that plays a significant role in the cell cycle. The expression and interaction of Bcl2 family proteins in T lymphocytes varies depending on their differentiation and activation status. M

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Adjumain, Shazia, Claire Xin Sun, Gabrielle Bradshaw, et al. "HGG-53. MULTI-DIMENSIONAL INTEGRATIVE PROFILING IDENTIFIES BCL2L1 METHYLATION AS A PREDICTIVE BIOMARKER FOR MCL-1 ACTIVITY IN PEDIATRIC HIGH-GRADE GLIOMAS." Neuro-Oncology 26, Supplement_4 (2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.337.

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Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs) pose a significant challenge as the most aggressive central nervous system tumors in children. The lack of effective treatment and poor survival rates emphasize the critical need for innovative therapies to improve the prognosis of pediatric patients with pHGG. METHODS We executed CRISPR-cas9 knockout (KO) screenings in 65 pediatric and 10 adult high-grade glioma (HGG) cell lines to explore unique functional dependencies associated with pHGGs. Drug assays were carried out to assess the targetability of a gene dependency of interest in pH

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Arribas, Alberto J., Byungsan Choi, Elisa Civanelli, et al. "Abstract 1878: Profiling protein-protein interactions to predict sensitivity to drugs targeting BCL2 family members in lymphoma models." Cancer Research 85, no. 8_Supplement_1 (2025): 1878. https://doi.org/10.1158/1538-7445.am2025-1878.

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Abstract Introduction: Pharmacological inhibition of anti-apoptotic proteins, especially with BCL2 inhibitors (i), has proven its clinical efficacy for treating patients with hematological cancers. However, there are not yet widely available tools to predict the sensitivity of individual patients to the different drugs targeting BCL2, MCL1, or BCLXL. A new technology, Single-molecule Protein Interaction Detection (SPID), based on immunoprecipitation of anti-apoptotic proteins followed by the addition of fluorescently labeled probes and detection at single-molecule accuracy, has shown promising

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Wu, Shihua, Feng Liu, Liming Xie, et al. "miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/365273.

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Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1

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Siu, Ka Tat, Cherrie Huang, Cristina Panaroni, et al. "Overcoming MCL1 Resistance in Multiple Myeloma." Blood 132, Supplement 1 (2018): 472. http://dx.doi.org/10.1182/blood-2018-99-116377.

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Abstract Disruption of the intrinsic apoptotic pathway by the aberrant expression of the BCL2 family members are frequent events in multiple myeloma (MM). The anti-apoptotic protein myeloid cell leukemia-1 (MCL1) is highly expressed in MM and plays a crucial role in disease progression. Inhibition of MCL1, thus, represents a unique therapeutic opportunity for the control of the disease. Currently, there is no FDA-approved drug with the ability to selectively target MCL1. Because of its pivotal role in MM, MCL1 is considered a high-value therapeutic target in the clinic. In this report, we use

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Haas, Marion, Gersende Caron, Fabrice Chatonnet, et al. "PIM2 kinase has a pivotal role in plasmablast generation and plasma cell survival, opening up novel treatment options in myeloma." Blood 139, no. 15 (2022): 2316–37. http://dx.doi.org/10.1182/blood.2021014011.

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Abstract The differentiation of B cells into plasmablasts (PBs) and then plasma cells (PCs) is associated with extensive cell reprogramming and new cell functions. By using specific inhibition strategies (including a novel morpholino RNA antisense approach), we found that early, sustained upregulation of the proviral integrations of Moloney virus 2 (PIM2) kinase is a pivotal event during human B-cell in vitro differentiation and then continues in mature normal and malignant PCs in the bone marrow. In particular, PIM2 sustained the G1/S transition by acting on CDC25A and p27Kip1 and hindering c

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Gui, Jingang, Zhuting Hu, Ching-Yi Tsai, et al. "MCL1 Enhances the Survival of CD8+Memory T Cells after Viral Infection." Journal of Virology 89, no. 4 (2014): 2405–14. http://dx.doi.org/10.1128/jvi.02480-14.

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ABSTRACTViral infection results in the generation of massive numbers of activated effector CD8+T cells that recognize viral components. Most of these are short-lived effector T cells (SLECs) that die after clearance of the virus. However, a small proportion of this population survives and forms antigen-specific memory precursor effector cells (MPECs), which ultimately develop into memory cells. These can participate in a recall response upon reexposure to antigen even at protracted times postinfection. Here, antiapoptotic myeloid cell leukemia 1 (MCL1) was found to prolong survival upon T cell

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Fultang, Norman, Brian Vidal, Ashley M. Schwab, et al. "Abstract 6147: MCL1 inhibitor PRT1419 demonstrates anti-tumor activity in PBRM1-altered clear cell renal cancer and synergizes with standard of care agents." Cancer Research 83, no. 7_Supplement (2023): 6147. http://dx.doi.org/10.1158/1538-7445.am2023-6147.

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Abstract Induced myeloid leukemia cell differentiation protein (MCL1) is a member of the B-cell lymphoma-2 (BCL2) family of apoptosis regulators, which plays a critical role in maintaining cellular homeostasis and promoting cancer cell survival. Increased expression of MCL1 in various cancers has been associated with poor prognosis and resistance to chemotherapeutic and targeted agents. We previously described PRT1419, a novel, potent, selective MCL1 inhibitor that demonstrates anti-tumor efficacy in various preclinical models of solid and hematologic malignancies. PRT1419 is currently under e

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Li, Ka Leung, Sarah C. Bray, Diana Iarossi, et al. "Investigation of a Novel Cyclin-Dependent-Kinase (CDK) Inhibitor Cdki-73 As an Effective Treatment Option for MLL-AML." Blood 126, no. 23 (2015): 1365. http://dx.doi.org/10.1182/blood.v126.23.1365.1365.

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Abstract The Acute Myeloid Leukemia (AML) subtype characterised by translocations of the Mixed-Lineage Leukemia gene, MLL (t11q23; MLL-AML), is a particularly devastating disease with a median overall survival of only 9 months with current standard therapy. Cyclin dependent kinase (CDK) 9 inhibitors (CDK9i) directly target the CDK9/cyclin T complex (pTEFb) that is essential for activity of the MLL-fusion proteins and for transcriptional elongation, and therefore leads to reduction of transcript levels for multiple key leukemic oncogenes e.g. HOXA9, MYC and MCL1. Several observations suggest th

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Faizan, Md Imam, Rituparna Chaudhuri, Shakti Sagar, et al. "NSP4 and ORF9b of SARS-CoV-2 Induce Pro-Inflammatory Mitochondrial DNA Release in Inner Membrane-Derived Vesicles." Cells 11, no. 19 (2022): 2969. http://dx.doi.org/10.3390/cells11192969.

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Circulating cell-free mitochondrial DNA (cf-mtDNA) has been found in the plasma of severely ill COVID-19 patients and is now known as a strong predictor of mortality. However, the underlying mechanism of mtDNA release is unexplored. Here, we show a novel mechanism of SARS-CoV-2-mediated pro-inflammatory/pro-apoptotic mtDNA release and a rational therapeutic stem cell-based approach to mitigate these effects. We systematically screened the effects of 29 SARS-CoV-2 proteins on mitochondrial damage and cell death and found that NSP4 and ORF9b caused extensive mitochondrial structural changes, out

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Philip, Sarah J., Valeria Visconte, Hetty E. Carraway, et al. "Significance of the Apoptotic Regulators BAX, BCL2, BCL- XL and MCL1 in Newly Diagnosed AML." Blood 142, Supplement 1 (2023): 5995. http://dx.doi.org/10.1182/blood-2023-185081.

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Introduction: In acute myeloid leukemia (AML), cytogenetics and molecular mutations remain important prognostic tools for tailoring treatment after induction therapy. Abnormalities in multiple components of apoptotic pathways have been identified as potential drivers of AML. Identifying other biomarkers may help us further refine prognosis and identify other therapeutic strategies. B-cell lymphoma 2 (Bcl2), Bcl-xL and myeloid cell leukemia-1 (Mcl1) are commonly expressed prosurvival proteins in hematologic malignancies, whereas Bax acts as a promoter of apoptosis. We retrospectively evaluated

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Sharon, David, Paul Jung, Yan Sun, et al. "Abstract 2530: DELE1 loss and dysfunctional integrated stress signaling in TP53 mutated AML is a novel pathway for venetoclax resistance." Cancer Research 83, no. 7_Supplement (2023): 2530. http://dx.doi.org/10.1158/1538-7445.am2023-2530.

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Abstract Background: Venetoclax (ven) in combination with hypomethylating agents or low dose cytarabine leads to rapid and durable remission in patients (pts) with acute myeloid leukemia (AML) unfit for intensive chemotherapy (IC), however, pts with TP53 mutations (TP53mut) exhibit adverse prognosis. Here, we identify dysregulation of the integrated stress response (ISR) pathway in pts with TP53mut, specifically through the actions of DAP3 binding cell death enhancer 1 (DELE1) and its activating protease OMA1. Methods: RNA sequencing was performed on pre-treatment bone marrow-derived mononucle

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Lin, Ying-Chun, Yu-Chia Chen, Rui-Yun Chen, et al. "Genomic Biomarkers of Survival in Patients with Adenocarcinoma of the Uterine Cervix Receiving Chemoradiotherapy." International Journal of Molecular Sciences 21, no. 11 (2020): 4117. http://dx.doi.org/10.3390/ijms21114117.

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This study investigated the prognostic effects of genomic biomarkers for predicting chemoradiotherapy (CRT)-based treatment outcomes in patients with adenocarcinoma (AC) of the uterine cervix. In all, 21 patients receiving definitive CRT were included. In accordance with the International Federation of Gynecology and Obstetrics (FIGO) staging system, 5, 8, and 8 patients were classified as having stage IB3, II, and III disease, respectively. Pretreatment biomarkers were analyzed using tissue microarrays from biopsy specimens. Genomic alterations were examined by next-generation sequencing (NGS

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Gill, Harinder, Ine Moors, Kimmo Porkka, et al. "A First in Human Study of VOB560 in Combination with MIK665 in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma, Acute Myeloid Leukemia, or Multiple Myeloma." Blood 144, Supplement 1 (2024): 5997. https://doi.org/10.1182/blood-2024-199074.

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Background: Patients with relapsed and refractory (R/R) acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM) require effective treatment options due to their high mortality rates. The inhibition of 2 anti-apoptotic proteins, B-cell lymphoma 2 (BCL2) and myeloid cell leukemia 1 (MCL1), has shown promise as a therapeutic approach for these cancers. Two novel BH3 mimetics, VOB560 and MIK665, selectively inhibit BCL2 and MCL1, respectively, induce apoptosis in hematological cancer cells and showed efficacy in preclinical models. In combination, VOB560 and MIK665 demo

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McGriff, Anna, and William J. Placzek. "Phylogenetic analysis of the MCL1 BH3 binding groove and rBH3 sequence motifs in the p53 and INK4 protein families." PLOS ONE 18, no. 1 (2023): e0277726. http://dx.doi.org/10.1371/journal.pone.0277726.

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B-cell lymphoma 2 (Bcl-2) proteins are central, conserved regulators of apoptosis. Bcl-2 family function is regulated by binding interactions between the Bcl-2 homology 3 (BH3) motif in pro-apoptotic family members and the BH3 binding groove found in both the pro-apoptotic effector and anti-apoptotic Bcl-2 family members. A novel motif, the reverse BH3 (rBH3), has been shown to interact with the anti-apoptotic Bcl-2 homolog MCL1 (Myeloid cell leukemia 1) and have been identified in the p53 homolog p73, and the CDK4/6 (cyclin dependent kinase 4/6) inhibitor p18INK4c, (p18, cyclin-dependent kina

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Wang, Weixin, Meghan Corrigan-Cummins, Donald C. Vinh, et al. "MCL-1 and Mir-181c in GATA2 Mutation Associated Monomac and Familial Myelodysplastic Syndrome." Blood 120, no. 21 (2012): 3807. http://dx.doi.org/10.1182/blood.v120.21.3807.3807.

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Abstract Abstract 3807 Background: Somatic and germline mutations in GATA2 were recently identified in patients diagnosed with MonoMAC, the hallmarks of which include mono cytopenia, B-cell and NK-cell lymphopenia, susceptibility to opportunistic infections (e.g. MAC), and a strong propensity to develop hypocellular MDS/AML or CMML. GATA2 mutations were also recently identified in other related disorders: Emberger syndrome (primary lymphedema with myelodysplasia), Familial MDS/AML, and DCML (Dendritic Cell, Monocytes, Lymphoid Deficiency). Family members with GATA2 mutations show variable pene

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Valiulienė, Giedrė, Aida Vitkevičienė, Giedrė Skliutė, Veronika Borutinskaitė, and Rūta Navakauskienė. "Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling." Molecules 26, no. 8 (2021): 2303. http://dx.doi.org/10.3390/molecules26082303.

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Metabolic landscape and sensitivity to apoptosis induction play a crucial role in acute myeloid leukemia (AML) resistance. Therefore, we investigated the effect of metformin, a medication that also acts as an inhibitor of oxidative phosphorylation (OXPHOS), and MCL-1 inhibitor S63845 in AML cell lines NB4, KG1 and chemoresistant KG1A cells. The impact of compounds was evaluated using fluorescence-based metabolic flux analysis, assessment of mitochondrial Δψ and cellular ROS, trypan blue exclusion, Annexin V-PI and XTT tests for cell death and cytotoxicity estimations, also RT-qPCR and Western

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Jia, Jiaoyuan, Li Che, Antonio Cigliano, et al. "Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis." International Journal of Molecular Sciences 21, no. 22 (2020): 8467. http://dx.doi.org/10.3390/ijms21228467.

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Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogene

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Klanova, Magdalena, and Pavel Klener. "BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas." Cancers 12, no. 4 (2020): 938. http://dx.doi.org/10.3390/cancers12040938.

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The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in

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Do Nascimento, Mariane Cristina, Diego A. Pereira-Martins, Guilherme Augusto Sousa Alcântara, et al. "Cephalochromin-Induced Mitochondrial Damage Overcomes Venetoclax-Resistance in Acute Myeloid Leukemia Models." Blood 142, Supplement 1 (2023): 5751. http://dx.doi.org/10.1182/blood-2023-189814.

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The combination of the BCL2 inhibitor venetoclax (VEN) with hypomethylating agents (e.g. azacytidine, AZA) significantly increased complete remission (CR) rates and prolonged overall survival of adults with Acute Myeloid Leukemia (AML) who were ineligible to intensive chemotherapy. However, VEN+AZA is not a curative treatment and resistance to VEN and/or relapses are common. Therefore, the search for new agents able to improve the depth and duration of CR or to overcome VEN resistance are needed. Cephalochromin (CPC), a natural compound easily obtained from Comospora vilior, emerges as a poten

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Dubois, Josephine, Kai Wu, Darren King, et al. "AML Blasts Intrinsic Interferon Production Causes Resistance to Venetoclax in Human Acute Myeloid Leukemia Via Upregulation of MCL1, BCL2A1 and BCL-XL." Blood 144, Supplement 1 (2024): 4151. https://doi.org/10.1182/blood-2024-203424.

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Introduction: Despite achievement of complete remission (CR) following chemotherapy, Acute Myelogenous Leukemia (AML) relapses in the majority of adult patients. The identification of cellular and molecular mechanisms that underlie resistance, persistence, and competitive regrowth of leukemic cells is of high interest to improve the outcome of AML patients. In this study, we have investigated the consequences of sterile leukemic inflammation on acquired novel properties and therapy resistance in human AML. Methods: Using single cell RNA sequencing we analyzed twenty paired AML specimens procur

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Bollino, Dominique, Andrea Casildo, Xinrong Ma, Kayla M. Tighe, Brandon Carter-Cooper, and Ashkan Emadi. "Long-Acting E. coli-Derived Asparaginase Potentiates the Anti-Leukemic Effect of BCL2 Inhibition, but Not MCL1 Inhibition, in Preclinical Models of Acute Myeloid Leukemia." Blood 142, Supplement 1 (2023): 5739. http://dx.doi.org/10.1182/blood-2023-178850.

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Background: Asparaginases are enzymes that deplete circulating asparagine and glutamine from plasma and can therefore be used therapeutically for cancers that are sensitive to amino acid depletion. Commercially available asparaginases are isolated fromeither E. coli or Erwinia chrysanthemi (also called crisantaspase), the latter having a higher glutaminase activity. Our previous studies have shown that pegcrisantaspase (PegC), a long-acting pegylated crisantaspase, synergizes with the BCL2 inhibitor, Venetoclax (Ven), to kill several AML cell lines and patient-derived primary AML cells with co

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Mukherjee, Nabanita, Carol M. Amato, Jenette Skees, et al. "Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma." Cancers 12, no. 8 (2020): 2182. http://dx.doi.org/10.3390/cancers12082182.

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There is an urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations. This is often the case in patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma. Here, we analyzed data from the cutaneous melanoma The Cancer Genome Atlas Network (TCGA) transcriptomic and proteomic databases for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations. Our data indicated higher B-cell CLL/lymphoma 2 (BCL2) expre

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Chen, Xingyong, Xiaogeng Shi, Xu Zhang, et al. "Scutellarin Attenuates Hypertension-Induced Expression of Brain Toll-Like Receptor 4/Nuclear Factor Kappa B." Mediators of Inflammation 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/432623.

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Hypertension is associated with low-grade inflammation, and Toll-like receptor 4 (TLR4) has been shown to be linked to the development and maintenance of hypertension. This study aimed to investigate the effects of scutellarin (administered by oral gavage daily for 2 weeks) on brain TLR4/nuclear factor kappa B-(NF-κB-) mediated inflammation and blood pressure in renovascular hypertensive (using the 2-kidney, 2-clip method) rats. Immunofluorescence and western immunoblot analyses revealed that hypertension contributed to the activation of TLR4 and NF-κB, accompanied by significantly enhanced ex

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