TY - JOUR
T1 - Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis
AU - van den Boom, Vincent
AU - Maat, Henny
AU - Geugien, Marjan
AU - Rodríguez López, Aida
AU - Sotoca, Ana M.
AU - Jaques, Jennifer
AU - Brouwers-Vos, Annet Z.
AU - Fusetti, Fabrizia
AU - Groen, Richard W.J.
AU - Yuan, Huipin
AU - Martens, Anton C.M.
AU - Stunnenberg, Hendrik G.
AU - Vellenga, Edo
AU - Martens, Joost H.A.
AU - Schuringa, Jan Jacob
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/1/12
Y1 - 2016/1/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84955387038&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.12.034
DO - 10.1016/j.celrep.2015.12.034
M3 - Article
C2 - 26748712
AN - SCOPUS:84955387038
SN - 2211-1247
VL - 14
SP - 332
EP - 346
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -