Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome

BCOR, encoding BCL-6 corepressor (BCOR), is X-linked and targeted by somatic mutations in various hematological malignancies including myelodysplastic syndrome (MDS). We previously reported that mice lacking Bcor exon 4 (BcorE4/y) in the hematopoietic compartment developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking Bcor exons 9 and 10 (BcorE9-10/y), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. BcorE9-10/y mice developed lethal T-ALL in a similar manner to BcorE4/y mice, whereas BcorE9-10/y hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2. Tet2/BcorE9-10/y mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2/BcorE9-10/y MDS cells reproduced MDS or evolved into lethal MDS/myeloproliferative neoplasms in secondary recipients. Transcriptional profiling revealed the derepression of myeloid regulator genes of the Cebp family and Hoxa cluster genes in BcorE9-10/y progenitor cells and the activation of p53 target genes specifically in MDS erythroblasts where massive apoptosis occurred. Our results reveal a tumor suppressor function of BCOR in myeloid malignancies and highlight the impact of Bcor insufficiency on the initiation and progression of MDS.

Source: Blood - December 6, 2018 Category: Hematology Authors: Tara, S., Isshiki, Y., Nakajima-Takagi, Y., Oshima, M., Aoyama, K., Tanaka, T., Shinoda, D., Koide, S., Saraya, A., Miyagi, S., Manabe, I., Matsui, H., Koseki, H., Bardwell, V. J., Iwama, A. Tags: Hematopoiesis and Stem Cells, Myeloid Neoplasia Source Type: research