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 Rodriguez Lopez, 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Article number102435
Number of pages29
JournaliScience
Volume24
Issue number5
DOIs
Publication statusPublished - 21-May-2021

Keywords

  • ACUTE MYELOID-LEUKEMIA
  • CELL SELF-RENEWAL
  • POLYCOMB GROUP
  • H2A UBIQUITYLATION
  • COMPLEX KARYOTYPE
  • USP7 INHIBITION
  • FAMILY-MEMBERS
  • CPG ISLANDS
  • STEM-CELLS
  • CBX FAMILY

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