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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 Examination of 5 histone marks, MLL, AF4, ENL and CFP1 in t(4;11) cells

ORGANISM(S): Homo sapiens

SUBMITTER: Thomas Milne

PROVIDER: E-GEOD-74812 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

2015-12-17 | GSE74812 | GEO

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

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

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

Genome-wide analysis of H3K79 dimethylation in MLL-AF4 leukemic bone marrow

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). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison

2008-11-04 | GSE12362 | 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.

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Genome-wide analysis of H3K79 dimethylation in normal and MLL-AF4 leukemic pre-B cells

2008-11-04 | GSE12361 | GEO

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (ChIP-seq)

Project description:Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.

2019-05-30 | GSE117864 | GEO