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Relevant bibliographies by topics / Leukemic Gene Expression Regulation

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Academic literature on the topic 'Leukemic Gene Expression Regulation'

Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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Journal articles on the topic "Leukemic Gene Expression Regulation"

1

Kettyle, Laura M., Charles-Étienne Lebert-Ghali, Ivan V. Grishagin, Glenda J. Dickson, Paul G. O’Reilly, David A. Simpson, Janet J. Bijl, Ken I. Mills, Guy Sauvageau, and Alexander Thompson. "Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia." Cancers 11, no. 12 (December 17, 2019): 2036. http://dx.doi.org/10.3390/cancers11122036.

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High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation.

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2

Serio, Justin, Wei Chen, Maria Mysliwski, Lili Chen, James Ropa, Jingya Wang, and Andrew G. Muntean. "The PAF Complex Regulation of Prmt5 Facilitates Leukemic Progression." Blood 128, no. 22 (December 2, 2016): 3914. http://dx.doi.org/10.1182/blood.v128.22.3914.3914.

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Abstract Acute myeloid leukemias have been linked with dysregulated epigenetic landscapes sometimes attributed to altered functions of epigenetic regulators. The Polymerase-Associated Factor complex (PAFc) is an epigenetic regulator involved in transcriptional initiation, elongation and termination and directly interacts with the CTD of RNA Pol II. The complex is comprised of 6 subunits in human cells, Paf1, Cdc73, Ctr9, Leo1, Rtf1 and Ski8. Many of these subunits have key roles in a variety of cancers including acute myeloid leukemia (AML). We have previously shown the relevance of the PAFc in MLL-rearranged leukemias where its interaction with MLL fusion-proteins is required for leukemic progression in vitro and in vivo (Muntean et al. 2013 Blood, Muntean et al. 2010 Cancer Cell). However, little is known about the gene programs controlled by the PAFc and how these contribute to leukemogenesis. Here we identify Prmt5, an arginine methyltransferase, as a direct downstream target gene of the PAFc. Prmt5 is upregulated in variety of cancers and has been linked to cell cycle progression and activation of known oncoproteins. In addition, Prmt5 has been implicated in AML and is essential for normal hematopoiesis where loss of Prmt5 induces bone marrow aplasia due to impaired cytokine signaling (Tarighat et al. 2015 Leukemia, Liu et al. 2015 J Clin Invest). Our work establishes a major role for the PAFc in regulating Prmt5 expression in AML. We observe that excision of the Cdc73 subunit of the PAFc results in reduced proliferation, the induction of differentiation, cell cycle arrest, and a mild increase in apoptosis. Several key epigenetic marks are reduced globally upon loss of Cdc73 including H4R3me2s, a modification catalyzed by Prmt5. RNA sequencing and bioinformatics analysis using GSEA, revealed that loss of Cdc73 led to increased expression of a gene program associated with hematopoietic differentiation, in agreement with our cellular characterization. In addition, the downregulation of a methyltransferase gene program was detected upon Cdc73 excision. Included in this signature were several members of the Prmt family. Analysis of changes in expression following loss of Cdc73 and functional relevance in MLL-AF9 leukemic cells led us to Prmt5 as a gene critically important in AML cells and modulated by the PAFc. To interrogate the function of Prmt5 in AML cells, we performed shRNA knockdown experiments which resulted in reduced proliferation, reduced cell fitness, G1 cell cycle arrest and global reduction H4R3me2s. ChIP experiments revealed that the PAFc localizes to the Prmt5 locus in mouse and human derived leukemic cells. Further, preliminary data suggests the MLL-AF9 fusion protein also localizes to the Prmt5 locus and may enhance its transcriptional output. The enzymatic activity of Prmt5 is necessary for AML cell growth as wild type PRMT5 can rescue proliferation of Prmt5 knock-down cells while a catalytic dead mutant cannot. Furthermore, we have observed that knockdown of Prmt5 increases the disease latency of Hoxa9/Meis1 induced leukemia in vivo. Utilizing a commercially available inhibitor for Prmt5, EPZ015666 (Chan-Pembre et al. 2015 Nat Chem Bio), we show pharmacologic inhibition of PRMT5 reduces the growth of a spectrum of human leukemic cell lines, suggesting PRMT5 is important for multiple subtypes of AML. Overall, our findings elucidate the PAFc as a regulator of Prmt5 expression that is necessary for the maintenance of AML. Disclosures No relevant conflicts of interest to declare.

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3

Gan, TE, PE Dadonna, and BS Mitchell. "Genetic expression of adenosine deaminase in human lymphoid malignancies." Blood 69, no. 5 (May 1, 1987): 1376–80. http://dx.doi.org/10.1182/blood.v69.5.1376.1376.

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Abstract Adenosine deaminase (ADA) is an enzyme in the purine catabolic pathway that has been used as an enzymatic marker of T cell lymphoblastic malignancies due to its high specific activity in thymocytes and immature T cells. We have investigated whether the level of ADA activity in lymphoid leukemic cells correlates with the amount of ADA- specific RNA and/or immunoreactive protein in these cells as an initial step toward characterizing the nature of the genetic regulation of ADA expression during differentiation. We have found a good correlation between the steady state levels of ADA-specific RNA and ADA- immunoreactive protein in T lymphoblastic leukemic cell lines, mature T cell lines, a B lymphoblast cell line, and leukemic cells directly isolated from four patients with acute lymphoblastic leukemia and three patients with chronic lymphocytic leukemia. Southern blot analysis of DNA from these cells shows no evidence for differences in ADA gene copy number or gene rearrangement to account for the variability in ADA expression. We conclude that levels of ADA in lymphoid leukemic cells are directly related to the amount of ADA-specific mRNA present. These findings imply that ADA expression in leukemic cells reflects either the transcriptional activity of the ADA gene or the stability of ADA mRNA in these cells.

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4

Gan, TE, PE Dadonna, and BS Mitchell. "Genetic expression of adenosine deaminase in human lymphoid malignancies." Blood 69, no. 5 (May 1, 1987): 1376–80. http://dx.doi.org/10.1182/blood.v69.5.1376.bloodjournal6951376.

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Adenosine deaminase (ADA) is an enzyme in the purine catabolic pathway that has been used as an enzymatic marker of T cell lymphoblastic malignancies due to its high specific activity in thymocytes and immature T cells. We have investigated whether the level of ADA activity in lymphoid leukemic cells correlates with the amount of ADA- specific RNA and/or immunoreactive protein in these cells as an initial step toward characterizing the nature of the genetic regulation of ADA expression during differentiation. We have found a good correlation between the steady state levels of ADA-specific RNA and ADA- immunoreactive protein in T lymphoblastic leukemic cell lines, mature T cell lines, a B lymphoblast cell line, and leukemic cells directly isolated from four patients with acute lymphoblastic leukemia and three patients with chronic lymphocytic leukemia. Southern blot analysis of DNA from these cells shows no evidence for differences in ADA gene copy number or gene rearrangement to account for the variability in ADA expression. We conclude that levels of ADA in lymphoid leukemic cells are directly related to the amount of ADA-specific mRNA present. These findings imply that ADA expression in leukemic cells reflects either the transcriptional activity of the ADA gene or the stability of ADA mRNA in these cells.

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5

Rosenbauer, Frank, Steffen Koschmieder, Ulrich Steidl, and Daniel G. Tenen. "Effect of transcription-factor concentrations on leukemic stem cells." Blood 106, no. 5 (September 1, 2005): 1519–24. http://dx.doi.org/10.1182/blood-2005-02-0717.

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Abstract Increasing evidence suggests that leukemias are sustained by leukemic stem cells. However, the molecular pathways underlying the transformation of normal cells into leukemic stem cells are still poorly understood. The involvement of a small group of key transcription factors into this process was suggested by their frequent mutation or down-regulation in patients with acute myeloid leukemia (AML). Recent findings in mice with hypomorphic transcription-factor genes demonstrated that leukemic stem-cell formation in AML could directly be caused by reduced transcription-factor activity beyond a critical threshold. Most interestingly, those experimental models and the paucity of biallelic null mutations or deletions in transcription-factor genes in patients suggest that AML is generally associated with graded down-regulation rather than complete disruption of transcription factors. Here, we discuss the effects of transcription-factor concentrations on hematopoiesis and leukemia, with a focus on the regulation of transcription-factor gene expression as a major mechanism that alters critical threshold levels during blood development and cancer.

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6

Resar, Linda, Joelle Hillion, Surajit Dhara, Takita Felder Sumter, Mita Mukherjee, Francescopaolo Di Cello, Amy Belton, et al. "The HMGA1a-STAT3 axis: an “Achilles Heel” for Hematopoietic Malignancies Overexpressing HMGA1a?" Blood 112, no. 11 (November 16, 2008): 3810. http://dx.doi.org/10.1182/blood.v112.11.3810.3810.

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Abstract Although the high mobility group A1 (HMGA1) oncogene is widely overexpressed in high-risk hematopoietic malignancies and other aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. The HMGA1 gene encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. We showed that HMGA1 induces leukemic transformation in cultured human lymphoid cells. Inhibiting HMGA1 expression blocks the transformed phenotype in cultured human leukemia and lymphoma cells. We also engineered HMGA1a transgenic mice and all mice develop aggressive lymphoid malignancy which closely models human T-cell acute lymphoblastic leukemia. Because HMGA1 participates in transcriptional regulation, we hypothesize that it drives leukemic transformation by dysregulating specific molecular pathways. To discover genes targeted by HMGA1 in leukemic transformation, we performed gene expression profile analysis. The signaltransducer andactivator oftranscription 3 (STAT3) gene was identified as a critical downstream target of HMGA1. STAT3 mRNA and protein are up-regulated in leukemic cells overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a. HMGA1a binds directly to a conserved region of the STAT3 promoter in vivo and activates transcription of the STAT3 promoter in human leukemia cells. Blocking STAT3 function with a small molecule, platinum compound inhibitor (CPA-7) induces apoptosis in leukemic cells from HMGA1 transgenic mice, but not in control cells. In primary, human leukemia samples, there is a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function with a dominant-negative construct in human leukemia or lymphoma cells leads to decreased cellular motility and colony formation. We also showed that treatment with a small molecule, oligonucleotide inhibitor decreases the leukemic burden in the HMGA1a transgenic mice. Our results demonstrate that the HMGA1a-STAT3 axis is a potential “Achilles heel” that could be exploited therapeutically in selected hematopoietic malignancies.

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7

Cheruku, Patali S., Marina Bousquet, Guoqing Zhang, Guangtao Ge, Wei Ying, Cong Meng, Andrew Shie, et al. "MiR-150 Inhibits MLL-AF9 Associated Leukemia By Suppressing Leukemic Stem Cells." Blood 122, no. 21 (November 15, 2013): 3764. http://dx.doi.org/10.1182/blood.v122.21.3764.3764.

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Abstract Leukemic stem cells (LSCs) are derived from hematopoietic stem or progenitor cells and often share gene expression patterns and specific pathways. Characterization and mechanistic studies of LSCs are critical as they are responsible for the initiation and potential relapse of leukemias, however the overall framework, including epigenetic regulation, is not yet clear. We previously identified microRNA-150 (miR-150) as a critical regulator of mixed lineage leukemia (MLL) -associated leukemias by targeting oncogenes. Our additional results suggest that miR-150 can inhibit LSC survival and disease initiating capacity by suppressing more than 30% of “stem cell signature genes,” hence altering multiple cancer pathways and/or stem cell identities. MLL-AF9 cells derived from miR-150 deficient hematopoietic stem/progenitor cells displayed significant proliferating advantage and enhanced leukemic colony formation. Whereas, with ectopic miR-150 expression, the MLL-AF9 associated LSC population (defined as Lin-ckit+sca1- cells) was significantly decreased in culture. This is further confirmed by decreased blast leukemic colony formation in vitro. Furthermore, restoration of miR-150 levels in transformed MLL-AF9 cells, which often display loss of miR-150 expression in AML patients with MLL-fusion protein expressing, completely blocked the myeloid leukemia development in a transplantation mouse model. Gene profiling analysis demonstrated that an increased level of miR-150 expression down regulates 30 of 114 stem cell signature genes by more than 1.5 fold, partially mediated by the suppressive effects of miR-150 on CBL, c-Myb and Egr2 oncogenes. In conclusion, our results suggest that miR-150 is a potent MLL-AF9 leukemic inhibitor that may act by suppressing the survival and leukemic initiating potency of MLL-AF9 LSCs. Disclosures: No relevant conflicts of interest to declare.

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Palmi, Chiara, Grazia Fazio, Ilaria Brunati, Valeria Cazzaniga, Valentina André, Silvano Sozzani, Antonello Villa, et al. "TEL-AML1 Affects the Regulation of Cytoskeleton and Causes Alteration In Cellular Adhesive and Migratory Properties In An In Vitro Model of Pre-Leukemia." Blood 116, no. 21 (November 19, 2010): 3624. http://dx.doi.org/10.1182/blood.v116.21.3624.3624.

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Abstract Abstract 3624 Introduction: The t(12;21) chromosome translocation generating TEL-AML1 chimeric fusion gene is a frequent initiating event in childhood leukaemia. Its impact is to generate a clone of covert, clinically silent pre-leukemic B cell progenitors. The leukemia arises only following second, post-natal hit/genetic events occurring years later. Moreover, relapse of leukemia is frequently arising from the pre-leukemic clone. Aim of our study is to investigate how TEL-AML1 expression can sustain this covert condition for many years. In a recent paper we described that the fusion gene rendered the B precursors resistant to the inhibitory activity of TGFbeta. Here we want to inquire into other factors that can explain the positive selection of the pre-leukemic clones over the normal counterpart. In particular, given the importance of the interaction with the microenvironment for survival signals for normal and leukemic stem cells, we question if the fusion gene causes changes in cellular adhesive and migratory properties. Methods: the study was performed by using two different models: i) a TEL-AML1 inducible expression system on the murine pro-B Ba/F3 cell line and ii) murine primary B lymphocytes (pre-BI cells) isolated from fetal liver, stably transduced with the pMIGR1-TEL-AML1-IRES-GFP construct. Gene expression assays were performed by using TaqMan (Applied Biosystems) and PCR Array technologies (SABioscences). Results: The expression of TEL-AML1 in Ba/F3 cell line causes over-expression of genes regulators of the cytoskeleton, specifically involved in cellular movement and in the regulation of actin dynamics. This gene expression alteration results in changes in the cellular morphology and phenotype: the cells acquire long extensions and several molecules involved in cell adhesion and migration are disregulated. Moreover, the TEL-AML1 positive cells present an increased ability to adhere to the ICAM1 substrate, but they also show a significant defect in the chemotactic response to CXCL12 in transwell migration assays in vitro, although the expression and the recycling of CXCR4 receptor are unaffected. This inability is not due to defects to migrate in general, as spontaneous motility is enhanced, but it is associated with a defect in CXCR4 signaling. In particular, CXCL12 calcium flux and ERK phosphorylation were inhibited. Those results have been confirmed in murine PreBI primary cells. Conclusions: in our murine models, TEL-AML1 affects the cytoscheleton regulation and causes alteration in cellular adhesive and migratory properties. We are now investigating how these alterations can give advantages to the pre-leukemic cells in the pathogenesis of TEL-AML1–expressing leukemia. Disclosures: No relevant conflicts of interest to declare.

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Reikvam, Håkon. "Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics." Cells 9, no. 7 (July 12, 2020): 1677. http://dx.doi.org/10.3390/cells9071677.

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Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.

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Jiang, Xiaoyan, Yun Zhao, Wing-Yiu Chan, Suzanne Vercauteren, Emily Pang, Sean Kennedy, Frank Nicolini, Allen Eaves, and Connie Eaves. "Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia." Blood 103, no. 10 (May 15, 2004): 3897–904. http://dx.doi.org/10.1182/blood-2003-11-4026.

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Abstract Ahi-1/AHI-1 (Abelson helper integration site-1) encodes a family of protein isoforms containing one Src homology 3 (SH3) domain and multiple tryptophan-aspartic acid 40 (WD40)–repeat domains. The function of these proteins is unknown, but involvement in leukemogenesis has been suggested by the high frequency of Ahi-1 mutations seen in certain virus-induced murine leukemias. Here we show that in both mice and humans, Ahi-1/AHI-1 expression is highest in the most primitive hematopoietic cells with specific patterns of down-regulation in different lineages. Cells from patients with chronic myeloid leukemia (CML; n = 28) show elevated AHI-1 transcripts in all disease phases and, in chronic phase, in the leukemic cells at all stages of differentiation, including quiescent (G0) CD34+ cells as well as terminally differentiating cells. In the most primitive lin–CD34+CD38– CML cells, transcripts for the 2 shorter isoforms of AHI-1 are also increased. Although 15 of 16 human lymphoid and myeloid leukemic cell lines showed aberrant control of AHI-1 expression, this was not seen in blasts obtained directly from patients with acute Philadelphia chromosome–negative (Ph–) leukemia (n = 15). Taken together, our results suggest that down-regulation of AHI-1 expression is an important conserved step in primitive normal hematopoietic cell differentiation and that perturbations in AHI-1 expression may contribute to the development of specific types of human leukemia.

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Dissertations / Theses on the topic "Leukemic Gene Expression Regulation"

1

Kuchinskaya, Ekaterina. "Genetic studies of acute lymphoblastic leukemia /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-337-5/.

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Lok, Chun-nam, and 陸振南. "Regulation of transferrin receptor expression in human leukemic HL-60 cells: gene expression and cellular signaling." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1996. http://hub.hku.hk/bib/B31235141.

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Lok, Chun-nam. "Regulation of transferrin receptor expression in human leukemic HL-60 cells : gene expression and cellular signaling /." Hong Kong : University of Hong Kong, 1996. http://sunzi.lib.hku.hk/hkuto/record.jsp?B17310659.

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4

Roos, Cecilia. "Studies of leukotriene C4 synthase expression and regulation in chronic myeloid leukaemia /." Karlstad : Faculty of Technology and Science, Biomedical Science, Karlstads universitet, 2008. http://www.diva-portal.org/kau/abstract.xsql?dbid=1598.

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Fält, Susann. "Analysis of global gene expression in complex biological systems using microarray technology /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-612-3/.

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Schiemann, William Paul. "Determination and characterization of leukemia inhibitory factor receptor signal transduction systems /." Thesis, Connect to this title online; UW restricted, 1996. http://hdl.handle.net/1773/6277.

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Xue, Liting. "Oncogene Function in Pre-Leukemia Stage of INV(16) Acute Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/740.

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The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells. Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block. N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively). Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels. In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals. My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.

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8

Xue, Liting. "Oncogene Function in Pre-Leukemia Stage of INV(16) Acute Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/740.

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Abstract:

The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells. Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block. N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively). Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels. In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals. My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.

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9

Bartoe, Joseph L. "The regulation of LIF- and CNTF-mediated signal transduction /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/6256.

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Fan, Kin-pong, and 范健邦. "The expression, regulation and functional role of SOX7 gene in acute myeloid leukemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45902914.

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Books on the topic "Leukemic Gene Expression Regulation"

1

Galos, Eli B. Viral gene expression regulation. New York: Nova Biomedical Books, 2010.

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Ma, Jun, ed. Gene Expression and Regulation. New York, NY: Springer New York, 2006. http://dx.doi.org/10.1007/978-0-387-40049-5.

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Perdew, Gary H., John P. Vanden Heuvel, and Jeffrey M. Peters, eds. Regulation of Gene Expression. Totowa, NJ: Humana Press, 2007. http://dx.doi.org/10.1007/978-1-59745-228-1.

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Travers, Helen. Oncogene regulation of gene expression. Manchester: University of Manchester, 1996.

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Ilan, Joseph, ed. Translational Regulation of Gene Expression. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5365-2.

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Feldmann, Marc, and Andrew McMichael, eds. Regulation of Immune Gene Expression. Totowa, NJ: Humana Press, 1986. http://dx.doi.org/10.1007/978-1-4612-5014-2.

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Clayton, R. M., and D. E. S. Truman, eds. Coordinated Regulation of Gene Expression. Boston, MA: Springer US, 1986. http://dx.doi.org/10.1007/978-1-4613-2245-0.

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Chan, Yvonne. Epigenetic regulation of enos gene expression. Ottawa: National Library of Canada, 1998.

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Williams, Graham R. Thyroid hormone regulation of gene expression. Austin: R.G. Landes, 1994.

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P, Vanden Heuvel John, and Peters Jeffrey M, eds. Regulation of gene expression: Molecular mechanisms. Totowa, N.J: Humana Press, 2006.

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Book chapters on the topic "Leukemic Gene Expression Regulation"

1

Spychala, Jozef, and Beverly S. Mitchell. "Regulation of Low Km (Ecto) 5’-Nucleotidase Gene Expression in Leukemic Cells." In Purine and Pyrimidine Metabolism in Man VIII, 683–87. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2584-4_142.

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Fernández-Mejia, C., O. Peralta-Zaragoza, J. Cerezo-Roman, C. Navarro-Duque, R. Barrera-Rodríguez, H. Martínez-Valdez, and V. Madrid-Marina. "Regulation of Gene Expression of Adenosine Deaminase, Purine Nucleoside Phosphorylase and Terminal Deoxynucleotidyl Transferase by Dexamethasone and cAMP in Human Leukemic Cells." In Purine and Pyrimidine Metabolism in Man VIII, 249–52. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2584-4_52.

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Beato, Miguel. "Gene Regulation by Steroid Hormones." In Gene Expression, 43–75. Boston, MA: Birkhäuser Boston, 1993. http://dx.doi.org/10.1007/978-1-4684-6811-3_3.

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Ross, Dennis W. "Gene Regulation and Expression." In Introduction to Molecular Medicine, 17–26. New York, NY: Springer New York, 1996. http://dx.doi.org/10.1007/978-1-4757-2460-8_2.

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Shah, Neel Jayesh. "Regulation of Gene Expression." In Introduction to Basics of Pharmacology and Toxicology, 381–85. Singapore: Springer Singapore, 2019. http://dx.doi.org/10.1007/978-981-32-9779-1_28.

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Ross, Dennis W. "Gene Expression and Regulation." In Introduction to Molecular Medicine, 22–34. New York, NY: Springer New York, 2002. http://dx.doi.org/10.1007/978-0-387-22521-0_2.

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Chedrese, Pedro J. "Regulation of Gene Expression." In Reproductive Endocrinology, 51–65. Boston, MA: Springer US, 2009. http://dx.doi.org/10.1007/978-0-387-88186-7_5.

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Santillán, Moisés. "Gene Expression and Regulation." In Lecture Notes on Mathematical Modelling in the Life Sciences, 91–106. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/978-3-319-06689-9_8.

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Ross, Dennis W. "Gene Regulation and Expression." In Introduction to Molecular Medicine, 19–27. New York, NY: Springer New York, 1992. http://dx.doi.org/10.1007/978-1-4757-4076-9_2.

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Frelinger, J. G., and M. J. Owen. "Control of MHC Gene Expression." In Immune Regulation, 79–80. Totowa, NJ: Humana Press, 1985. http://dx.doi.org/10.1007/978-1-4612-4996-2_10.

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Conference papers on the topic "Leukemic Gene Expression Regulation"

1

Ding, Yali, Bo Zhang, Jonathon L. Payne, Kimberly J. Payne, Chunhua Song, Chandrika Gowda, Soumya Iyer, et al. "Abstract 2620: Global epigenetic regulation of gene expression and tumor suppression in T-cell leukemia by Ikaros." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2620.

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Ding, Yali, Bo Zhang, Jonathon L. Payne, Kimberly J. Payne, Chunhua Song, Chandrika Gowda, Soumya Iyer, et al. "Abstract 2620: Global epigenetic regulation of gene expression and tumor suppression in T-cell leukemia by Ikaros." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2620.

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Loaec, Morgann, Jonathon Payne, Elanora Dovat, Chunhua Song, Kimberly J. Payne, and Sinisa Dovat. "Abstract 4463: Epigenetic regulation of gene expression in high-risk B-cell acute lymphoblastic leukemia by Casein Kinase II." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4463.

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Hasty, Jeff. "Stochastic regulation of gene expression." In Stochastic and chaotic dynamics in the lakes. AIP, 2000. http://dx.doi.org/10.1063/1.1302384.

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Lu, Xinhua, Jigui Sun, Ying Ren, and Shuai Lu. "The Regulation of Gene Expression in E-Cell." In Third International Conference on Natural Computation (ICNC 2007). IEEE, 2007. http://dx.doi.org/10.1109/icnc.2007.737.

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Roy, Sourav. "Hormonal regulation of gene expression patterns in mosquito reproduction." In 2016 International Congress of Entomology. Entomological Society of America, 2016. http://dx.doi.org/10.1603/ice.2016.93884.

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Han, Xiaosong, Xinhua Lu, Chunguo Wu, and Yanchun Liang. "Gene Expression Regulation in E-Cell Model Analog-Cell." In 2010 Fifth International Conference on Frontier of Computer Science and Technology (FCST). IEEE, 2010. http://dx.doi.org/10.1109/fcst.2010.80.

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Kwon, Andrew T., Holger H. Hoos, and Raymond Ng. "Inference of transcriptional regulation relationships from gene expression data." In the 2003 ACM symposium. New York, New York, USA: ACM Press, 2003. http://dx.doi.org/10.1145/952532.952561.

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Aleem, Hosam A., Ferda Mavituna, and David H. Green. "A Galois Field Approach to Modelling Gene Expression Regulation." In 2008 38th International Symposium on Multiple Valued Logic (ismvl 2008). IEEE, 2008. http://dx.doi.org/10.1109/ismvl.2008.35.

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MARGALIT, HANAH. "REGULATION OF GENE EXPRESSION BY SMALL NON-CODING RNAS." In Proceedings of the 18th International Conference. PUBLISHED BY IMPERIAL COLLEGE PRESS AND DISTRIBUTED BY WORLD SCIENTIFIC PUBLISHING CO., 2007. http://dx.doi.org/10.1142/9781860949852_0019.

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Reports on the topic "Leukemic Gene Expression Regulation"

1

Geballe, Adam. Translational Regulation of HER2 Gene Expression. Fort Belvoir, VA: Defense Technical Information Center, December 1997. http://dx.doi.org/10.21236/ada339298.

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Rodenhiser, David I. Transcriptional Regulation and Targeting of NF1 Gene Expression. Fort Belvoir, VA: Defense Technical Information Center, October 2001. http://dx.doi.org/10.21236/ada407208.

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Kuchka, M. R. Post transcriptional regulation of chloroplast gene expression by nuclear encoded gene products. Office of Scientific and Technical Information (OSTI), January 1992. http://dx.doi.org/10.2172/7309627.

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Kuchka, M. R. Post transcriptional regulation of chloroplast gene expression by nuclear encoded gene products. Office of Scientific and Technical Information (OSTI), January 1992. http://dx.doi.org/10.2172/5268747.

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Kuchka, M. R. Post-transcriptional regulation of chloroplast gene expression by nuclear encoded gene products. Office of Scientific and Technical Information (OSTI), August 1999. http://dx.doi.org/10.2172/764181.

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Levine, R. P. The Regulation of Gene Expression in Cnidarian-Algal Associations. Fort Belvoir, VA: Defense Technical Information Center, July 1998. http://dx.doi.org/10.21236/ada349126.

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Guerinot, M. L. (Iron regulation of gene expression in the Bradyrhizobium japonicum/soybean symbiosis). Office of Scientific and Technical Information (OSTI), January 1992. http://dx.doi.org/10.2172/5312051.

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Braam, Janet. Genetic analysis of the regulation of TCH gene expression, Final Report. Office of Scientific and Technical Information (OSTI), October 2008. http://dx.doi.org/10.2172/939904.

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Xiao, Hua. Regulation of Estrogen-Responsive Gene Expression and Tumor Suppression by Transcriptional Cofactors. Fort Belvoir, VA: Defense Technical Information Center, May 2005. http://dx.doi.org/10.21236/ada437873.

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Karen S. Browning, Marie Petrocek, and Bonnie Bartel. The 5th Symposium on Post-Transcriptional Regulation of Plant Gene Expression (PTRoPGE). Office of Scientific and Technical Information (OSTI), June 2006. http://dx.doi.org/10.2172/889783.

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