The Global H3K4 Methylation State Controls Leukemia Stem Cell Fate

Global changes in the epigenetic landscape have been suggested to contribute to tumorigenesis in various types of cancer, but whether the epigenome specifically regulates the function of cancer stem cells remains unclear. Using chromatin immunoprecipitation sequencing, Wong and colleagues compared the genome-wide epigenetic landscape of c-KIT–positive enriched leukemia stem cells (LSC) and c-KIT–negative differentiated cells in MLL-rearranged acute myeloid leukemia (AML). This analysis revealed that, in contrast to c-KIT–negative cells, LSCs were characterized by global hypermethylation of histone 3 lysine 4 (H3K4) and hypomethylation of H3K79. In addition, increased levels of H3K4 dimethylation and trimethylation (H3K4me3) were present on MLL target genes that promote AML pathogenesis and LSC maintenance genes in LSCs, whereas reduced H3K4me3 correlated with downregulation of the LSC transcriptional program in c-KIT–negative cells, suggesting that LSC self-renewal and oncogenic potential are negatively regulated by reversion of this epigenetic profile. Consistent with this idea, expression of the H3K4 histone lysine (K)-specific demethylase 5B (KDM5B) was increased in c-KIT–negative differentiated cells compared with LSCs. Overexpression of KDM5B diminished genome-wide H3K4me3, induced differentiation, and inhibited the growth of MLL-transformed and human MLL-rearranged leukemia cells, but not leukemia cells transformed by non-MLL oncogenes, both in vitro and in vivo. Conversely, KDM5B depletion enhanced H3K4me3 levels, increased the expression of LSC maintenance genes, and augmented bone marrow engraftment and leukemia aggressiveness in xenotransplantation models. These findings provide evidence that the global H3K4 methylation state modulates LSC differentiation and demonstrate that KDM5B functions as a tumor suppressor in MLL-associated AML by suppressing the oncogenic potential of LSCs.

Wong SH, Goode DL, Iwasaki M, Wei MC, Kuo HP, Zhu L, et al. The H3K4-methyl epigenome regulates leukemia stem cell oncogenic potential. Cancer Cell 2015;28:198–209.

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