The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia
Henny Maat,
Tjerk Jan Atsma,
Shanna M. Hogeling,
Aida Rodríguez López,
Jennifer Jaques,
Mirjam Olthuis,
Marcel P. de Vries,
Chantal Gravesteijn,
Annet Z. Brouwers-Vos,
Nisha van der Meer,
Suzan Datema,
Jonas Salzbrunn,
Gerwin Huls,
Roy Baas,
Joost H.A. Martens,
Vincent van den Boom,
Jan Jacob Schuringa
Affiliations
Henny Maat
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Tjerk Jan Atsma
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Shanna M. Hogeling
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Aida Rodríguez López
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Jennifer Jaques
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Mirjam Olthuis
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Marcel P. de Vries
Department of Pharmacy, Interfaculty Mass Spectrometry Center, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands; Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Chantal Gravesteijn
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Annet Z. Brouwers-Vos
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Nisha van der Meer
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Suzan Datema
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Jonas Salzbrunn
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Gerwin Huls
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Roy Baas
Division of Biochemistry and Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
Joost H.A. Martens
Department of Molecular Biology, RIMLS, Radboud University, Nijmegen, The Netherlands
Vincent van den Boom
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; Corresponding author
Jan Jacob Schuringa
Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; Corresponding author
Summary: In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients.
