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Targeting epigenetic networks mediated by Prmt1 and Kdm4c in acute myeloid leukemia

ABSTRACT: Transcriptional deregulation plays a major role in acute myeloid leukemia, identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence showing the functional involvement and therapeutic potentials of targeting PRMT1 with H4R3 methyltransferase activity in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C with H3K9 demethylase activity by chimeric transcription factors to mediate epigenetic reprogramming. Inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a novel and targetable epigenetic circuitry mediated by PRMT1 and KDM4C in acute leukemia.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Mus musculus

SUBMITTER: Jayant Rane

PROVIDER: E-MTAB-3322 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The genome wide mapping of H3K9 and H3K23 acetylation in Moz+/+ and Moz-/- MOZ-TIF2 AML cells

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Targeting epigenetic networks mediated by Prmt1 and Kdm4c in acute myeloid leukemia

Project description:Targeting epigenetic networks mediated by Prmt1 and Kdm4c in acute myeloid leukemia

| PRJEB8535 | ENA

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2015-08-04 | E-GEOD-71688 | biostudies-arrayexpress

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

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

Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia

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.

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

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