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Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells [ChIP-Seq]

ABSTRACT: Identification of histone acetylation targets of Kat2a activity in murine models of acute myeloid leukemia (AML) driven by the MLL-AF9 oncogenic fusion

ORGANISM(S): Mus musculus

PROVIDER: GSE118576 | GEO | 2020/02/03

REPOSITORIES: GEO

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Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells [RNA-Seq]

Project description:Identification of histone acetylation targets of Kat2a activity in murine models of acute myeloid leukaemia (AML) driven by the MLL-AF9 oncogenic fusion

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Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells.

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Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells

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Hes1 is responsible for Notch signaling-mediated suppression of acute myeloid leukemia development

Project description:In leukemogenesis Notch signaling can be up- and down-regulated in a context-dependent manner. Here we report that deletion of hairy and enhancer of split-1 (Hes1) promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. Subsequently, the FMS-like tyrosine kinase 3 (FLT3) was up-regulated in mouse cells of a Hes1- or RBP-J-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development by down-regulating FLT3 expression. 4 samples are analyzed, two pairs of MLL-AF9/Hes1-/- and MLL-AF9/Hes1+/+ leukemic bone marrows.

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Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells

Project description:This SuperSeries is composed of the SubSeries listed below.

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RNA sequencing expression analysis of murine MLL-AF9;NRAS acute myeloid leukemia cells silenced for E2-2.

Project description:We investigated the role of the transcriptional regulators Id2 and E2-2 (encoded by Tcf4) in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by a Tet-off inducible MLL-AF9 allele co-expressed with oncogenic NRASG12D, we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in MLL-AF9 AML cells results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. E2-2 silencing phenocopies Id2 overexpression in MLL-AF9-AML cells. To study the gene expression changes associated with E2-2 depletion in the context of MLL-rearranged AML, RNA sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen). Primary AMLs driven by MLL/AF9 expression linked to cherry reporter, in association with oncogenic NRASG12D (MLL/AF9;NRAS) were generated by reconstituting lethally irradiated congenic mice with fetal liver cells co-transduced with the MSCV-MLL/AF9-IRES-cherry retroviral vector and a second vector co-expressing NRASG12D together with luciferase (MSCV-luciferase-IRES-NRASG12D). RNA sequencing analysis sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced in vitro with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen) linked to the reporter GFP. Viable GFP-positive cells were FACS-sorted 2 days after transduction and used for RNA sequencing analysis. Two independent biological replicates of the experiment were used for the RNA sequencing (9-5-14 and 14-4-14).

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