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Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [ATAC-Seq]

ABSTRACT: Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises approximately 10% of all AML cases and portends poor outcomes. Much remains to be uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a highly expressed gene with a super-enhancer MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia patient samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects in MLL-r AML. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block in MLL-r AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165979 | GEO | 2021/10/02

REPOSITORIES: GEO

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Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [RNA-Seq]

Project description:Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises approximately 10% of all AML cases and portends poor outcomes. Much remains to be uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a highly expressed gene with a super-enhancer MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia patient samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects in MLL-r AML. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block in MLL-r AML.

2021-10-03 | GSE165981 | GEO

Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [ChIP-Seq]

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Gene expression change after inactivation of MEF2D or PU.1 by CRISPR-Cas9

Project description:Transcriptional dysregulation is a prominent feature in leukemia. Here, we systematically surveyed the transcription factor (TF) vulnerabilities in leukemia, and uncovered TF clusters that exhibit context-specific addictions within and between different subtypes of leukemia. We focused on and validated MEF2D as a requirement exclusively in AML with high IRF8 expression. Transcriptomic and chromatin-binding profiling revealed a key TF circuit composed of MEF2D-IRF8 vital for AML maintenance. AML can acquire dependence on this circuit through various mechanisms, including enhancer activation of the circuit via MLL-rearrangement. IRF8 cooperates with PU.1 to control PU.1/MEIS1 co-regulated transcriptional outputs, meanwhile coordinating with MEF2D to directly regulate genes in a non-redundant manner. Collectively, our study nominates a TF circuit in support of the pathogenesis of AML.

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Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia [CUT&RUN]

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Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia [ChIP-seq]

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CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors

Project description:The DNA hypomethylating drug decitabine maintains normal hematopoietic stem and progenitor cell (HSPC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. To better understand the basis for this contrasting treatment effect, the baseline expression of key lineage-specifying transcription factor (TF) (eg., CEBPa) and key late differentiation TF (CEBPe), was examined in normal, myelodysplastic (MDS) and AML primary cells and cell lines. To appreciate the role of differentiation in hypomethylation of some CpG by decitabine treatment but not others, promoter CpGs, analyzed by microarray and mass spectrometry, were categorized by the direction of methylation change during normal myeloid differentiation. In MDS/AML cells, high expression of CEBPa, relatively low expression of CEBPe (a gene target of CEBPa), hypermethylation of CEBPe promoter CpG, and the methylation pattern at differentiation sensitive promoter CpGs analyzed by microarray, suggested lineage-commitment and aberrant epigenetic repression of late differentiation genes. DNA hypomethylation in response to decitabine was greatest at CpGs that are hypomethylated during normal myeloid differentiation. In contrast, normal HSPC treated with decitabine retained immature morphology, and methylation significantly decreased at CpG that are hypermethylated during myeloid differentiation. Partial differentiation at baseline, and repression of key late differentiation genes by epigenetic means, likely plays a role in methylation and phenotype responses of AML cells treated with decitabine. Bisulphite converted DNA from the 208 samples were hybridised to the Illumina Cancel Panel 1 GPL9183 methylation assay

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Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia [Microarray expression]

Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.

2015-08-04 | E-GEOD-71687 | biostudies-arrayexpress

Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia

2014-09-17 | E-GEOD-61468 | biostudies-arrayexpress

CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors

2011-07-01 | GSE29047 | GEO

POLR2M-mediated paused transcription silences tumor suppressor MIR139 in MLL-AF9 AML

Project description:MIR139 is a critical tumor suppressor and commonly silenced in human cancer, including acute myeloid leukemia (AML). Here, we found that depletion of identified MIR139 targets affects AML outgrowth. We unraveled the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. Epigenetic analyses revealed two well-conserved putative enhancer regions in close proximity of transcriptional start sites (TSS) of MIR139. These regions were silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these regions abolished MIR139 transcriptional regulation in normal and oncogenic conditions. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139-silencing factor. Furthermore, direct POLR2M binding to the MIR139 TSS induced paused transcription, which was abrogated upon PRC2 inhibition. We present evidence for an oncogenic POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. Together, our findings highlight the importance of POLR2M-mediated paused transcription in AML.

2021-11-11 | PXD022488 | Pride

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