ABSTRACT
Polycomb proteins are essential epigenetic regulators of gene transcription. KDM2B, the chromatin-binding moiety of non-canonical PRC1.1, is critically important for human leukemias. Here, we investigated the complete interactome of KDM2B in human leukemic cells and identified that the deubiquitinase USP7 is an essential component of PRC1.1 and required for its stability and function. USP7 inhibition results in disassembly of the PRC1.1 complex and consequently loss of binding to its target loci. PRC1.1 can be associated with active loci and loss of PRC1.1 binding coincided with loss of H2AK119ub, reduced H3K27ac levels and reduced gene transcription, whereas H3K4me3 levels remained unaffected. Survival was reduced in (primary) acute myeloid leukemia cells in both cycling as well as quiescent populations upon USP7 inhibition, also independent of the USP7-MDM2-p53 axis. Finally, we evaluated the efficacy of USP7 inhibition in vivo and find that progression of MLL-AF9-induced leukemia is delayed, although in a niche-dependent manner.
