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High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML.
Zhao Y, Liu Q, Acharya P, Stengel KR, Sheng Q, Zhou X, Kwak H, Fischer MA, Bradner JE, Strickland SA, Mohan SR, Savona MR, Venters BJ, Zhou MM, Lis JT, Hiebert SW
(2016) Cell Rep 16: 2003-16
MeSH Terms: Antineoplastic Agents, Azepines, Cell Line, Tumor, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Clustered Regularly Interspaced Short Palindromic Repeats, DNA-Directed RNA Polymerases, Drug Resistance, Neoplasm, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute, MicroRNAs, Multigene Family, Myeloid Cell Leukemia Sequence 1 Protein, Promoter Regions, Genetic, Protein Isoforms, Proteins, Proto-Oncogene Proteins c-kit, Transcription, Genetic, Translocation, Genetic, Triazoles
Show Abstract · Added April 6, 2017
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways.
Smith S, Tripathi R, Goodings C, Cleveland S, Mathias E, Hardaway JA, Elliott N, Yi Y, Chen X, Downing J, Mullighan C, Swing DA, Tessarollo L, Li L, Love P, Jenkins NA, Copeland NG, Thompson MA, Du Y, Davé UP
(2014) PLoS One 9: e85883
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, CD2 Antigens, Carcinogenesis, Cell Line, Tumor, E-Box Elements, Gene Expression Regulation, Leukemic, Homeodomain Proteins, Humans, LIM Domain Proteins, Leukemia, T-Cell, Mice, Mice, Transgenic, Molecular Sequence Data, Neoplasm Proteins, Oncogenes, Penetrance, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Signal Transduction, Transcription Factors, Transcription, Genetic, Up-Regulation
Show Abstract · Added March 5, 2014
The LMO2 oncogene is deregulated in the majority of human T-cell leukemia cases and in most gene therapy-induced T-cell leukemias. We made transgenic mice with enforced expression of Lmo2 in T-cells by the CD2 promoter/enhancer. These transgenic mice developed highly penetrant T-ALL by two distinct patterns of gene expression: one in which there was concordant activation of Lyl1, Hhex, and Mycn or alternatively, with Notch1 target gene activation. Most strikingly, this gene expression clustering was conserved in human Early T-cell Precursor ALL (ETP-ALL), where LMO2, HHEX, LYL1, and MYCN were most highly expressed. We discovered that HHEX is a direct transcriptional target of LMO2 consistent with its concordant gene expression. Furthermore, conditional inactivation of Hhex in CD2-Lmo2 transgenic mice markedly attenuated T-ALL development, demonstrating that Hhex is a crucial mediator of Lmo2's oncogenic function. The CD2-Lmo2 transgenic mice offer mechanistic insight into concordant oncogene expression and provide a model for the highly treatment-resistant ETP-ALL subtype.
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27 MeSH Terms
Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients.
Gamazon ER, Lamba JK, Pounds S, Stark AL, Wheeler HE, Cao X, Im HK, Mitra AK, Rubnitz JE, Ribeiro RC, Raimondi S, Campana D, Crews KR, Wong SS, Welsh M, Hulur I, Gorsic L, Hartford CM, Zhang W, Cox NJ, Dolan ME
(2013) Blood 121: 4366-76
MeSH Terms: Antimetabolites, Antineoplastic, Apoptosis, Cytarabine, Drug Resistance, Neoplasm, Gene Expression Regulation, Leukemic, Genome-Wide Association Study, Genotype, Humans, Leukemia, Myeloid, Acute, Phenotype, Polymorphism, Single Nucleotide, Treatment Outcome
Show Abstract · Added February 22, 2016
A whole-genome approach was used to investigate the genetic determinants of cytarabine-induced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7- to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10(-5)) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n = 18) was significantly greater than expected by chance (P = .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P = 1.31 × 10(-6)) and AA (vs GA or GG) genotype was associated with poorer OS (P = .015), likely as a result of greater treatment-related mortality (P = .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084.
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12 MeSH Terms
Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia.
Aue G, Du Y, Cleveland SM, Smith SB, Davé UP, Liu D, Weniger MA, Metais JY, Jenkins NA, Copeland NG, Dunbar CE
(2011) Blood 118: 4674-81
MeSH Terms: Animals, Bone Marrow Transplantation, Cells, Cultured, Disease Models, Animal, Epistasis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Leukemic, HL-60 Cells, Haploinsufficiency, Humans, Leukemia, Myeloid, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microarray Analysis, Proto-Oncogene Proteins, SOXC Transcription Factors, Trans-Activators
Show Abstract · Added March 5, 2014
Cooperation of multiple mutations is thought to be required for cancer development. In previous studies, murine myeloid leukemias induced by transducing wild-type bone marrow progenitors with a SRY sex determining region Y-box 4 (Sox4)-expressing retrovirus frequently carried proviral insertions at Sfpi1, decreasing its mRNA levels, suggesting that reduced Sfpi1 expression cooperates with Sox4 in myeloid leukemia induction. In support of this hypothesis, we show here that mice receiving Sox4 virus-infected Sfpi1(ko/+) bone marrow progenitors developed myeloid leukemia with increased penetrance and shortened latency. Interestingly, Sox4 expression further decreased Sfpi1 transcription. Ectopic SOX4 expression reduced endogenous PU.1 mRNA levels in HL60 promyelocytes, and decreased Sfpi1 mRNA levels were also observed in the spleens of leukemic and preleukemic mice receiving Sox4 virus-infected wild-type bone marrow cells. In addition, Sox4 protein bound to a critical upstream regulatory element of Sfpi1 in ChIP assays. Such cooperation probably occurs in de novo human acute myeloid leukemias, as an analysis of 285 acute myeloid leukemia patient samples found a significant negative correlation between SOX4 and PU.1 expression. Our results establish a novel cooperation between Sox4 and reduced Sfpi1 expression in myeloid leukemia development and suggest that SOX4 could be an important new therapeutic target in human acute myeloid leukemia.
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18 MeSH Terms
Proleukemic RUNX1 and CBFbeta mutations in the pathogenesis of acute leukemia.
Engel ME, Hiebert SW
(2010) Cancer Treat Res 145: 127-47
MeSH Terms: Cell Transformation, Neoplastic, Core Binding Factor Alpha 2 Subunit, Core Binding Factor beta Subunit, Gene Expression Regulation, Leukemic, Hematopoiesis, Humans, Leukemia, Myeloid, Acute, Mutation, Neoplasm Proteins, Oncogene Proteins, Fusion, Transcription, Genetic, Translocation, Genetic
Show Abstract · Added March 7, 2014
The existence of non-random mutations in critical regulators of cell growth and differentiation is a recurring theme in cancer pathogenesis and provides the basis for our modern, molecular approach to the study and treatment of malignant diseases. Nowhere is this more true than in the study of leukemogenesis, where research has converged upon a critical group of genes involved in hematopoietic stem and progenitor cell self-renewal and fate specification. Prominent among these is the heterodimeric transcriptional regulator, RUNX1/CBFbeta. RUNX1 is a site-specific DNA-binding protein whose consensus response element is found in the promoters of many hematopoietically relevant genes. CBFbeta interacts with RUNX1, stabilizing its interaction with DNA to promote the actions of RUNX1/CBFbeta in transcriptional control. Both the RUNX1 and the CBFbeta genes participate in proleukemic chromosomal alterations. Together they contribute to approximately one-third of acute myelogenous leukemia (AML) and one-quarter of acute lymphoblastic leukemia (ALL) cases, making RUNX1 and CBFbeta the most frequently affected genes known in the pathogenesis of acute leukemia. Investigating the mechanisms by which RUNX1, CBFbeta, and their proleukemic fusion proteins influence leukemogenesis has contributed greatly to our understanding of both normal and malignant hematopoiesis. Here we present an overview of the structural features of RUNX1/CBFbeta and their derivatives, their roles in transcriptional control, and their contributions to normal and malignant hematopoiesis.
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12 MeSH Terms
Concordant gene expression in leukemia cells and normal leukocytes is associated with germline cis-SNPs.
French D, Yang W, Hamilton LH, Neale G, Fan Y, Downing JR, Cox NJ, Pui CH, Evans WE, Relling MV
(2008) PLoS One 3: e2144
MeSH Terms: Child, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Genotype, Germ-Line Mutation, Humans, Leukocytes, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma
Show Abstract · Added February 22, 2016
The degree to which gene expression covaries between different primary tissues within an individual is not well defined. We hypothesized that expression that is concordant across tissues is more likely influenced by genetic variability than gene expression which is discordant between tissues. We quantified expression of 11,873 genes in paired samples of primary leukemia cells and normal leukocytes from 92 patients with acute lymphoblastic leukemia (ALL). Genetic variation at >500,000 single nucleotide polymorphisms (SNPs) was also assessed. The expression of only 176/11,783 (1.5%) genes was correlated (p<0.008, FDR = 25%) in the two tissue types, but expression of a high proportion (20 of these 176 genes) was significantly related to cis-SNP genotypes (adjusted p<0.05). In an independent set of 134 patients with ALL, 14 of these 20 genes were validated as having expression related to cis-SNPs, as were 9 of 20 genes in a second validation set of HapMap cell lines. Genes whose expression was concordant among tissue types were more likely to be associated with germline cis-SNPs than genes with discordant expression in these tissues; genes affected were involved in housekeeping functions (GSTM2, GAPDH and NCOR1) and purine metabolism.
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9 MeSH Terms
Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53.
Irish JM, Anensen N, Hovland R, Skavland J, Børresen-Dale AL, Bruserud O, Nolan GP, Gjertsen BT
(2007) Blood 109: 2589-96
MeSH Terms: Cells, Cultured, DNA Damage, Electrophoresis, Gel, Two-Dimensional, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Humans, Leukemia, Myeloid, Acute, Mutation, Phosphorylation, Protein Isoforms, Proto-Oncogene Proteins c-bcl-2, Signal Transduction, Tumor Suppressor Protein p53, Tyrosine, fms-Like Tyrosine Kinase 3
Show Abstract · Added February 15, 2013
Loss or mutation of the TP53 tumor suppressor gene is not commonly observed in acute myeloid leukemia (AML), suggesting that there is an alternate route for cell transformation. We investigated the hypothesis that previously observed Bcl-2 family member overexpression suppresses wild-type p53 activity in AML. We demonstrate that wild-type p53 protein is expressed in primary leukemic blasts from patients with de novo AML using 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and phospho-specific flow cytometry. We found that p53 was heterogeneously expressed and phosphorylated in AML patient samples and could accumulate following DNA damage. Overexpression of antiapoptosis protein Bcl-2 in AML cells was directly correlated with p53 expression and phosphorylation on serine residues 15, 46, and 392. Within those patients with the highest levels of Bcl-2 expression, we identified a mutation in FLT3 that duplicated phosphorylation site Y591. The presence of this mutation correlated with greater than normal Bcl-2 expression and with previously observed profiles of potentiated STAT and MAPK signaling. These results support the hypothesis that Flt3-mediated signaling in AML enables accumulation of Bcl-2 and maintains a downstream block to p53 pathway apoptosis. Bcl-2 inhibition might therefore improve the efficacy of existing AML therapies by inactivating this suppression of wild-type p53 activity.
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16 MeSH Terms
Expression of cyclooxygenase-2 and prostaglandins by B-1 cells and B-CLL cells.
Phipps RP, Pollock SJ, Kaur K, Kaufman J, Borrello MA, Graf BA, Nazarenko D, Roberts LJ, Morrow JD, Palis J, Ryan DJ, Bennett JM
(2000) Curr Top Microbiol Immunol 252: 293-300
MeSH Terms: Animals, Antibodies, Anti-Idiotypic, B-Lymphocyte Subsets, CD40 Ligand, Cell Differentiation, Cyclooxygenase 1, Cyclooxygenase 2, Dinoprostone, Enzyme Induction, Gene Expression Regulation, Leukemic, Humans, Inflammation, Interferon-gamma, Isoenzymes, Leukemia, Lymphocytic, Chronic, B-Cell, Lipopolysaccharides, Lymphocyte Activation, Macrophages, Membrane Proteins, Mice, Neoplasm Proteins, Neoplastic Stem Cells, Prostaglandin-Endoperoxide Synthases, Prostaglandins, RNA, Messenger, Th2 Cells, Tumor Cells, Cultured
Added December 10, 2013
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27 MeSH Terms
Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway.
Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GW, Pendergast AM
(1998) Genes Dev 12: 1415-24
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Bone Marrow, Cysteine Endopeptidases, Cytoskeletal Proteins, Fusion Proteins, bcr-abl, Gene Expression Regulation, Leukemic, Homeodomain Proteins, Humans, Leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Multienzyme Complexes, Neoplasm Proteins, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-abl, Proto-Oncogene Proteins pp60(c-src), Tumor Cells, Cultured, Ubiquitins, ras Proteins
Show Abstract · Added March 11, 2014
Oncogenic forms of the Abl and Src tyrosine kinases trigger the destruction of the Abi proteins, a family of Abl-interacting proteins that antagonize the oncogenic potential of Abl after overexpression in fibroblasts. The destruction of the Abi proteins requires tyrosine kinase activity and is dependent on the ubiquitin-proteasome pathway. We show that degradation of the Abi proteins occurs through a Ras-independent pathway. Significantly, expression of the Abi proteins is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemias. These findings suggest that loss of Abi proteins may be a component in the progression of Bcr-Abl-positive leukemias and identify a novel pathway linking activated nonreceptor protein tyrosine kinases to the destruction of specific target proteins through the ubiquitin-proteasome pathway.
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22 MeSH Terms
Transcriptional regulation during myelopoiesis.
Lenny N, Westendorf JJ, Hiebert SW
(1997) Mol Biol Rep 24: 157-68
MeSH Terms: Animals, Gene Expression Regulation, Gene Expression Regulation, Developmental, Gene Expression Regulation, Leukemic, Hematopoiesis, Humans, Leukemia, Myeloid, Acute, Macrophages, Mice, Mice, Knockout, Monocytes, Transcription Factors
Show Abstract · Added June 10, 2010
The coordinated production of all blood cells from a common stem cell is a highly regulated process involving successive stages of commitment and differentiation. From analyses of mice deficient in transcription factor genes and from the characterizations of chromosome breakpoints in human leukemias, it has become evident that transcription factors are important regulators of hematopoiesis. During myelopoiesis, which includes the development of granulocytic and monocytic lineages, transcription factors from several families are active, including AML1/CBF beta, C/EBP, Ets, c-Myb, HOX, and MZF-1. Few of these factors are expressed exclusively in myeloid cells; instead it appears that they cooperatively regulate transcription of myeloid-specific genes. Here we discuss recent advances in transcriptional regulation during myelopoiesis.
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12 MeSH Terms