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MLL-rearranged acute lymphoblastic leukemias upregulate BCL-2 through H3K79 methylation and are highly sensitive to the BCL-2 specific antagonist ABT-199

ABSTRACT: We present ChIP-seq in the t(4;11) cell line SEM for different components of the MLL-AF4 complex as well as other chromatin proteins

ORGANISM(S): Homo sapiens

PROVIDER: GSE74812 | GEO | 2015/12/17

SECONDARY ACCESSION(S): PRJNA301600

REPOSITORIES: GEO

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MLL-rearranged acute lymphoblastic leukemias upregulate BCL-2 through H3K79 methylation and are highly sensitive to the BCL-2 specific antagonist ABT-199

Project description:We present ChIP-seq in the t(4;11) cell line SEM for different components of the MLL-AF4 complex as well as other chromatin proteins Examination of 5 histone marks, MLL, AF4, ENL and CFP1 in t(4;11) cells

2015-12-17 | E-GEOD-74812 | biostudies-arrayexpress

MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199.

Project description:Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199. We demonstrate that MLL/AF4 specifically upregulates the BCL-2 gene but not other BCL-2 family members via DOT1L-mediated H3K79me2/3. We use this information to show that a t(4;11) cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. In addition, ABT-199 synergizes with standard induction-type therapy in a xenotransplant model, advocating for the introduction of ABT-199 into therapeutic regimens for MLL-rearranged leukemias.

| S-EPMC4700051 | biostudies-literature

ChIP-seq of the HOXA9 and MEIS1 transcription factors in SEM cells.

Project description:SEM cells were established from the peripheral blood of a 5-year-old girl in relapse with acute lymphoblastic leukaemia (ALL). SEM cells exhibit the t(4;11) chromosomal rearrangement, which leads to production of the MLL-AF4 fusion protein. Hematopoietic transcription factors including HOXA9 and MEIS1 are highly expressed in ALL. ChIP-seq was performed against HoxA9 and MEIS1 in SEM cells. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing.

2012-05-31 | E-GEOD-38339 | biostudies-arrayexpress

ChIP-seq of the HOXA9 and MEIS1 transcription factors in SEM cells.

2012-05-31 | GSE38339 | GEO

ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development.

Project description:With the advent of new agents targeting CD20, Bruton's tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion. In this review, we summarized the latest clinical development of ABT-199/venetoclax and other novel agents targeting the BCL-2 proteins.

| S-EPMC4654800 | biostudies-literature

Instructive role of MLL fusion proteins revealed by a faithful model of t(4;11) proB acute lymphoblastic leukemia

Project description:The t(4;11)(q21;q23) fuses MLL to AF4, the most common MLL fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34+ cells to generate a faithful model of t(4;11) proB ALL that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a distinct B-ALL from MLL-AF9 through differential DNA binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. We observed this incongruity in t(4;11) patients who evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.

2016-11-23 | GSE84116 | GEO

H3K79 methylation profiles define murine and human MLL-AF4 leukemias

Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. This SuperSeries is composed of the SubSeries listed below.

2008-11-04 | GSE12363 | GEO

MLL-AF4 binds directly to a BCL-2 specific enhancer and impacts H3K27 acetylation

Project description:Survival rates for children diagnosed with acute lymphoblastic leukemia (ALL) have drastically improved, but those carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we showed that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. We went on to show that MLL leukemias are particularly sensitive to treatment with the BCL-2 inhibitor venetoclax which synergizes with both standard chemotherapeutic agents as well as DOT1L inhibitors. Altered expression of other BCL-2 family members is a major cause of resistance to ventoclax, so here we perform a detalied analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production, we find that of all the BCL-2 family genes, MLL-AF4 directly controls the transcription of both BCL-2 and MCL-1, but only BCL-2 shows a significant loss of steady state RNA levels. Interestingly however, both MCL-1 and BCL-XL protein levels are dependent on MLL-AF4 activity through an unknown and likely indirect mechanism. Finally, we analyze MLL-AF4 regulation of the BCL-2 gene in greater detail and using Capture C we identify a major BCL-2 specific enhancer consisting of two clusters of H3K27Ac. Loss of MLL-AF4 activity results in a reduction of H2K27Ac levels at the major BCL-2 enhancer, revealing a novel regulatory dependence on MLL-AF4 function at BCL-2.

2016-11-23 | GSE85988 | GEO

Targeting BCL-2 with the BH3 mimetic ABT-199 in ER-positive breast cancer

Project description:A bank of human breast tumor xenografts was established by serial passage of primary breast tumor fragments in the cleared mammary fat pads of immuno-compromised NOD-SCID-IL2Rgammac-/- mice. The expression profiles from four different tumors (23T, 315T, 50T and 838T) were classified using diagonal discriminant analysis. The training data set consisted of 1992 samples from Curtis et al. (2012, PMID: 22522925); class labels were based on tumor subtype information provided (Basal-like, Luminal A, Luminal B, HER2-enriched and Normal breast-like). Total RNA obtained from xenograft tumors from different patients have been profiled on the Illumina HT-12 BeadChip platform.

| S-ECPF-GEOD-47369 | biostudies-other

Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding.

Project description:Background and purposeAlthough the ongoing clinical trials of ABT-263 and ABT-199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge.Experimental approachThe LD50 values of ABT-737, ABT-263 and ABT-199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl-2 family proteins, including phosphorylated Bcl-2 (pBcl-2) and their interactions were measured by immunoblotting and co-immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed.Key resultsThe ratio of (Mcl-1 + pBcl-2) to Bcl-2 expression provided the most significant predictive marker for the cytotoxic potential of ABT-737, ABT-263 and ABT-199 in the panel of CLL samples. Mechanistically, pBcl-2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl-2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100-300-fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl-2 (T69E, S70E and S87E; EEE-Bcl-2). BH3 peptides exhibited different rank orders of binding affinities to full-length WT-Bcl-2 and full-length EEE-Bcl-2.Conclusions and implicationsOur study suggested that a structural alteration in the BH3-binding groove was induced by phosphorylation of Bcl-2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl-2 kinase inhibitors with the ABT compounds.

| S-EPMC4728412 | biostudies-literature

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