Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis

作者：van den Boom Vincent; Maat Henny; Geugien Marjan; Lopez Aida Rodriguez; Sotoca Ana M; Jaques Jennifer; Brouwers Vos Annet Z; Fusetti Fabrizia; Groen Richard W J; Yuan Huipin; Martens Anton C M; Stunnenberg Hendrik G; Vellenga Edo; Martens Joost H A; Schuringa Jan Jacob

来源：Cell Reports, 2016, 14(2): 332-346.

DOI：10.1016/j.celrep.2015.12.034

Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here, we find that the non-canonical PRC1.1 complex, as identified by mass-spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34(+) cells. Besides a set of genes that is targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3, suggesting a gene-regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls specific genes involved in unique cell biological processes required for leukemic cell viability.

• 出版日期2016-1-12