title: Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis.
abstract: 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.
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands.
authors.forename: Vincent
authors.initials: V
authors.lastname: van den Boom
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands.
authors.forename: Henny
authors.initials: H
authors.lastname: Maat
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands.
authors.forename: Marjan
authors.initials: M
authors.lastname: Geugien
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands.
authors.forename: Aida
authors.initials: A
authors.lastname: Rodríguez López
authors.affiliation: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sotoca
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jaques
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands.
authors.forename: Annet Z
authors.initials: AZ
authors.lastname: Brouwers-Vos
authors.affiliation: Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, Netherlands Proteomics Centre and Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, the Netherlands.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Fusetti
authors.affiliation: Department of Hematology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Groen
authors.affiliation: Xpand Biotechnology BV, Professor Bronkhorstlaan 10, 3723 MB Bilthoven, the Netherlands.
authors.forename: Huipin
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Hematology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
authors.forename: Anton C M
authors.initials: AC
authors.lastname: Martens
authors.affiliation: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands.
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.affiliation: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands.
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Martens
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands. Electronic address: j.j.schuringa@umcg.nl.
authors.forename: Jan Jacob
authors.initials: JJ
authors.lastname: Schuringa
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D063150:Polycomb Repressive Complex 1