KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in T-cell leukemogenesis. Mus musculus

KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 composes polycomb repressive complex 1.1 (PRC1.1), a non-canonical PRC1 that catalyzes H2AK119ub1. It binds to non-methylated CpG islands through its zinc finger-CxxC (CxxC-ZF) DNA binding domain and recruits the complex to the target gene loci. Recent studies have identified the loss of function mutations in PRC1.1 genes, BCOR and BCORL1 in human T-cell acute lymphoblastic leukemia (T-ALL). We previously reported that Bcor insufficiency induces T-ALL in mice, supporting a tumor suppressor role for Bcor. However, it remained to be clarified which function of BCOR accounts for the tumor suppressor function: the co-repressor function for BCL6 or the function as a component of PRC1.1. We herein analyzed mice lacking the CxxC-ZF domain of KDM2B specifically in hematopoietic cells. Like Bcor-deficient mice, Kdm2b-deficient mice developed lethal T-ALL that were mostly NOTCH1-dependent. ChIP sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, where BCOR and EZH2 co-localized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that non-canonical PRC1.1 antagonizes NOTCH1-mediated gene activation. Of interest, KDM2B target genes were expressed at higher levels than the others and were marked with high levels H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results suggest that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in T-cell leukemogenesis.