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H3K4me3 ChIP-Seq analysis of LSKs isolated from WT and Mll-PTD knock-in heterozygous mice

ABSTRACT: The MLL-PTD mutation is found in patients with MDS and AML, and not in other haematological malignancies. Previously, we showed that Mll-PTD knock-in heterozygous mice present with several MDS-associated features, such as increased self-renewal and apoptosis in HSPCs, expansion of the myeloid progenitor population, ineffective haematopoiesis, and skewed myeloid differentiation. MLL is an epigenetic regulator: its C-terminal Su[var]3–9, enhancer of zeste, trithorax (SET) domain has methyltransferase activity on lysine 4 on histone 3 (H3K4), which is retained in the MLL-PTD mutant. To clarify the effects of MLL-PTD on target gene regulation, we performed H3K4me3 ChIP-Seq analysis of LSKs isolated from WT and Mll-PTD knock-in heterozygous mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE75608 | GEO | 2018/12/01

REPOSITORIES: GEO

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MLL-PTD and RUNX1-knockout cooperate to induce MDS phenotypes

Project description:The MLL-PTD mutation is found in patients with MDS and AML, and not in other hematological malignancies. Previously, we showed that Mll-PTD knock-in heterozygous mice (MllPTD/WT mice) present with several MDS-associated features. However, these phenotypes are insufficient to constitute bona fide MDS. MllPTD/WT mice do not generate MDS or AML in primary or transplant recipient mice. This suggests that additional genetic and/or epigenetic defects are necessary for transformation to MDS or AML. In secondary AML and de novo AML, MLL-PTD mutation is significantly associated with mutations in RUNX1 and with the FLT3-ITD mutations. In fact, the combination of MLL-PTD with the FLT3-ITD allele leads to AML in mice. We combined the MLL-PTD with RUNX1 mutant proteins, in order to generate a new mouse model for MDS. We generated MllPTD/WT/Runx1Flox/Flox/Mx1-Cre mice to model loss-of-function RUNX1 mutations. To test the significance of HIF-1α in this model, we also generated MllPTD/WT/Runx1Flox/Flox/Hif-1αFlox/Flox/Mx1-Cre mice and genetically eliminated Hif-1α expression. We analyzed gene expression variations in the HSPCs comparing the MllPTD/WT/Runx1∆/∆ with or without HIF-1α abrogation.

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Project description:H3K4me3 ChIP-Seq analysis of LSKs isolated from WT and Mll-PTD knock-in heterozygous mice

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Effect of Dot1l deletion on LSKs and GMPs

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Transcription profiling of mouse hematopoietic cells (GMP, CMP, CLP and HSC), FACS sorted from wild type and Mll-AF9 knock-ins

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