Bcor insufficiency cooperates with Tet2 loss in the pathogenesis of myelodysplastic syndrome. Mus musculus

BCOR, encoding BCL-6 co-repressor (BCOR), is located on the X chromosome and targeted by somatic mutations in various hematological malignancies including myelodysplastic syndrome (MDS). We previously reported that mice lacking Bcor exon 4 (BcorDE4/y) developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking Bcor exons 9 and 10 (BcorDE9-10/y), which express BCOR truncated for the carboxyl-terminal domain for interaction with PCGF1, a core component of polycomb repressive complex (PRC) 1.1. While BcorDE9-10/y mice developed lethal T-ALL in a manner similar to BcorDE4/y mice, BcorDE9-10 hematopoietic cells showed a growth advantage in the myeloid compartment, which was further enhanced by concurrent deletion of Tet2. Notably, Tet2D/DBcorDE9-10 mice developed lethal MDS with progressive anemia and leukocytopenia and morphological dysplasia of blood cells. Tet2D/DBcorDE9-10 MDS cells reproduced MDS or evolved into lethal MDS/MPN in secondary recipients after serial transplantation. Transcriptional profiling revealed de-repression of myeloid regulator genes of Cebp family and Hoxa cluster genes in hematopoietic progenitor cells and p53 pathway genes in erythroblasts in the absence of Bcor. Our findings uncover a tumor suppressor function of BCOR in myeloid malignancies and highlight the impact of Bcor insufficiency in the initiation and progression of MDS.