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DNA-damage induced differentiation of leukemic cells as an anti-cancer barrier

ABSTRACT: Here we show that the histone methyltransferase MLL4 (Kmt2d) is required for stem cell activity and an aggressive form of acute myeloid leukemia (AML) harboring the MLL-AF9 oncogene. MLL4 exerts its function by regulating transcriptional programs associated with the anti-oxidant response. The role of Mll4 (Kmt2d) in regulating the transcriptome of primary and transformed hematopoietic stem cells was studied.

ORGANISM(S): Mus musculus

SUBMITTER: Robert Faryabi

PROVIDER: E-GEOD-57147 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.

Santos Margarida A MA Faryabi Robert B RB Ergen Aysegul V AV Day Amanda M AM Malhowski Amy A Canela Andres A Onozawa Masahiro M Lee Ji-Eun JE Callen Elsa E Gutierrez-Martinez Paula P Chen Hua-Tang HT Wong Nancy N Finkel Nadia N Deshpande Aniruddha A Sharrow Susan S Rossi Derrick J DJ Ito Keisuke K Ge Kai K Aplan Peter D PD Armstrong Scott A SA Nussenzweig André A

Nature 20140727 7520

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma, is required for stem-cell activity and an aggressive form of acute ...[more]

PMID: 25079327

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The Polycomb Repressive Complex 2 Is Required For MLL-AF9 Leukemia

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2012-02-22 | E-GEOD-34963 | biostudies-arrayexpress

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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.

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Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia

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2012-02-22 | E-GEOD-34959 | biostudies-arrayexpress

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2013-01-18 | E-GEOD-42260 | biostudies-arrayexpress

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2011-09-12 | E-GEOD-25911 | biostudies-arrayexpress

Genome-wide maps of C/EBPbeta, MLL4 and histone modifications in C/EBPbeta-overexpressed WT and MLL4-/- brown preadipocytes

Project description:Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for the deposition of H3K4me1/2 on enhancers remain elusive. Furthermore, the functions of these methyltransferases on enhancers and associated cell-type-specific gene expression are poorly understood. Here, we identify MLL4 (KMT2D) as a major H3K4 mono- and di-methyltransferase in mammalian cells. Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of MLL4 dramatically decreases H3K4me1/2 and H3K27ac on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Finally, we provide evidence that lineage-determining TFs recruit and require MLL4 to establish enhancers critical for cell-type-specific gene expression. Together, these results identify MLL4 as an H3K4 mono-/di-methyltransferase required for enhancer activation during cell differentiation. ChIP-Seq analyses of C/EBPbeta, MLL4 and histone modifications (H3K4me1, H3K27ac) in vec- or C/EBPbeta-overexpressing, adenoviral GFP- or Cre-infected, MLL3-/-MLL4-flox/flox brown preadipocytes without induction of differentiation.

2013-12-17 | E-GEOD-50455 | biostudies-arrayexpress

mRNA expression profiles of WT and MLL4-/- during brown preadipocyte differentiation

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