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 (Bcor DE4/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 (Bcor DE9-10/y ), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. Bcor D E9-10/y mice developed lethal T-ALL in a similar manner to Bcor DE4/y mice, whereas Bcor D E9-10/y hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2. Tet2 D / D Bcor D E9-10/y mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2 D / D Bcor D E9-10/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 Bcor DE9-10/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. (Blood. 2018;132(23): 2470-2483)
Bibliographical noteFunding Information:
This work was supported, in part, by Grants-in-Aid for Scientific Research (#15H02544) and Scientific Research on Innovative Areas “Stem Cell Aging and Disease” (#26115002) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and grants from the Yasuda Memorial Medical Foundation and Tokyo Biochemical Research Foundation.
The authors thank Noriko Yamanaka and Yuko Yamagata for their technical assistance, and Ola Mohammed Kamel Rizq for critically reviewing the manuscript. The supercomputing resource was provided by the Human Genome Center, The Institute of Medical Science, The University of Tokyo. This work was supported, in part, by Grants-in-Aid for Scientific Research (#15H02544) and Scientific Research on Innovative Areas “Stem Cell Aging and Disease” (#26115002) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and grants from the Yasuda Memorial Medical Foundation and Tokyo Biochemical Research Foundation.
Copyright 2011 by The American Society of Hematology; all rights reserved.