Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis
Vincent van den Boom,
Henny Maat,
Marjan Geugien,
Aida Rodríguez López,
Ana M. Sotoca,
Jennifer Jaques,
Annet Z. Brouwers-Vos,
Fabrizia Fusetti,
Richard W.J. Groen,
Huipin Yuan,
Anton C.M. Martens,
Hendrik G. Stunnenberg,
Edo Vellenga,
Joost H.A. Martens,
Jan Jacob Schuringa
Affiliations
Vincent van den Boom
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands
Henny Maat
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands
Marjan Geugien
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands
Aida Rodríguez López
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands
Ana M. Sotoca
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands
Jennifer Jaques
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands
Annet Z. Brouwers-Vos
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands
Fabrizia Fusetti
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
Richard W.J. Groen
Department of Hematology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
Huipin Yuan
Xpand Biotechnology BV, Professor Bronkhorstlaan 10, 3723 MB Bilthoven, the Netherlands
Anton C.M. Martens
Department of Hematology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
Hendrik G. Stunnenberg
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands
Edo Vellenga
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands
Joost H.A. Martens
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands
Jan Jacob Schuringa
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, the Netherlands
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.
