Journal article

The H3K4-Methyl Epigenome Regulates Leukemia Stem Cell Oncogenic Potential

Stephen HK Wong, David L Goode, Masayuki Iwasaki, Michael C Wei, Hsu-Ping Kuo, Li Zhu, Dominik Schneidawind, Jesus Duque-Afonso, Ziming Weng, Michael L Cleary

CANCER CELL | CELL PRESS | Published : 2015


The genetic programs that maintain leukemia stem cell (LSC) self-renewal and oncogenic potential have been well defined; however, the comprehensive epigenetic landscape that sustains LSC cellular identity and functionality is less well established. We report that LSCs in MLL-associated leukemia reside in an epigenetic state of relative genome-wide high-level H3K4me3 and low-level H3K79me2. LSC differentiation is associated with reversal of these broad epigenetic profiles, with concomitant downregulation of crucial MLL target genes and the LSC maintenance transcriptional program that is driven by the loss of H3K4me3, but not H3K79me2. The H3K4-specific demethylase KDM5B negatively regulates l..

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Awarded by Public Health Service (PHS) - National Cancer Institute

Awarded by German Research Foundation (Deutsche Forschungsgemeinschaft)

Awarded by PHS

Funding Acknowledgements

We thank Maria Ambrus and Cita Nicolas for technical assistance, members of the M.L.C. lab for helpful discussions, Anton Valouev for advice on ChIP-seq peak calling, and Kathy Sakamoto and Norman Lacayo for providing primary human MLLr cells. S.H.K.W. was supported by a Yong Investigator Award from the Alex's Lemonade Stand Foundation for Childhood Cancer. H.-P.K. was supported by Public Health Service (PHS) grants T32-CA09302 and T32-CA09151, awarded by the National Cancer Institute, U.S. Department of Health & Human Services, and Dean's Postdoctoral Fellowship at the Stanford School of Medicine. J.D.-A. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft DU 1287/2-1). D.S. was supported by the Dr. Mildred Scheel Fellowship of the German Cancer Aid. We acknowledge support from the Children's Health Initiative of the Packard Foundation and PHS grant CA116606.