The H3K4-methyl epigenome regulates MLL leukemia stem cell oncogenic potential. Mus musculus

The genetic programs that maintain leukemia stem cell (LSC) self-renewal and oncogenic potential have been well defined, however the epigenetic landscape that determines their cellular identity and functionality has not been established. We report that LSCs in MLL-associated leukemia are maintained in an epigenetic state defined by relative genome-wide high-level H3K4me3 methylation and low level H3K79me2. LSC differentiation is associated with dynamic reversal of these broad epigenetic profiles and concomitant down-regulation of the LSC maintenance transcriptional program. LSCs also share with embryonic stem cells a large subset of genes with bivalent histone marks related to embryonic development. The histone demethylase KDM5B negatively regulates MLL-induced leukemogenesis demonstrating the crucial role of the H3K4 global methylome for determining leukemia stem cell fate. Overall design: Investigation of multiple histone modification marks and RNA Pol II in ckit+ and ckit- cells isolated and fractionated from MLL leukemia mice.