KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis

Abstract

KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 comprise polycomb repressive complex 1.1 (PRC1.1), a noncanonical PRC1 that catalyzes H2AK119ub1. It binds to nonmethylated CpG islands through its zinc finger-CxxC DNA binding domain and recruits the complex to target gene loci. Recent studies identified the loss of function mutations in the PRC1.1 gene, 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, the function of BCOR responsible for tumor suppression, either its corepressor function for BCL6 or that as a component of PRC1.1, remains unclear. We herein examined mice specifically lacking the zinc finger-CxxC domain of KDM2B in hematopoietic cells. Similar to Bcor-deficient mice, Kdm2b-deficient mice developed lethal T-ALL mostly in a NOTCH1-dependent manner. A chromatin immunoprecipitation sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, at which BCOR and EZH2 colocalized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that noncanonical PRC1.1 antagonizes NOTCH1-mediated gene activation. KDM2B target genes were expressed at higher levels than the others and were marked with high levels of H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.

Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV

“…In addition, ChIP with IgG was used as a negative control to determine the background level of ChIPs while an intergenic region on the host genome (Neg) was used as an additional negative control for the ChIP assays. As a positive control for the KDM2B ChIP we used Myc promoter where KDM2B is known to bind (Fig 8D) [46]. Our results showed that the enrichment of KDM2B on the RTA promoter was gradually increased along with RYBP while the ChIP signal in the IgG ChIP samples and on the Neg region remained low indicating the specificity of KDM2B and RYBP ChIPs (Fig 8A).…”

Functional loss of a non-canonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation

“…For example, the PRC1.1 complex is also important in preventing T-cell acute lymphoblastic leukemia (T-ALL). Mice lacking the PUFD domain of BCOR (same floxed allele as present study) or the zinc finger domain of KDM2B both developed lethal T-ALL (Tara et al 2018;Isshiki et al 2019), suggesting a broader role for PRC1.1 as a tumor suppressor in cancer.…”

<p>Repression of PCGF1 Decreases the Proliferation of Glioblastoma Cells in Association with Inactivation of c-Myc Signaling Pathway</p>

“…23,24 Recent research has indicated that polycomb group members, such as EZH2, Bmi1, KDM2B, PHF19, SUZ12, CBX8, and so on, are involved in the proliferation of cancer cell including glioma cells. 20,[25][26][27][28][29][30][31] In the present study, we revealed the association between PCGF1 and various characteristics of glioblastoma (GBM).…”