Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome

Shiro Tara, Yusuke Isshiki, Yaeko Nakajima-Takagi, Motohiko Oshima, Kazumasa Aoyama, Tomoyuki Tanaka, Daisuke Shinoda, Shuhei Koide, Atsunori Saraya, Satoru Miyagi, Ichiro Manabe, Hirotaka Matsui, Haruhiko Koseki, Vivian J. Bardwell and Atsushi Iwama

Key points

  • Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome.

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


BCOR, encoding BCL-6 co-repressor (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 (BcorΔE4/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 (BcorΔE9-10/y), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex (PRC) 1.1. BcorΔE9-10/y mice developed lethal T-ALL in a similar manner to BcorΔE4/y mice, while BcorΔE9-10/y hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2. Tet2Δ/ΔBcorΔE9-10/y mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2Δ/ΔBcorΔE9-10/y MDS cells reproduced MDS or evolved into lethal MDS/MPN in secondary recipients. Transcriptional profiling revealed the de-repression of myeloid regulator genes of the Cebp family and Hoxa cluster genes in BcorΔE9-10/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.

  • Submitted January 17, 2018.
  • Accepted September 13, 2018.