| First Author | Tara S | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 23 | Pages | 2470-2483 |
| PubMed ID | 30228234 | Mgi Jnum | J:268780 |
| Mgi Id | MGI:6273115 | Doi | 10.1182/blood-2018-01-827964 |
| Citation | Tara S, et al. (2018) Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome. Blood 132(23):2470-2483 |
| abstractText | 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 (DeltaE4/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 (DeltaE9-10/y) ), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. Bcor (DeltaE9-10/y) mice developed lethal T-ALL in a similar manner to Bcor (DeltaE4/y) mice, whereas Bcor (DeltaE9-10/y) hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2 Tet2 (Delta/Delta) Bcor (DeltaE9-10/y) mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2 (Delta/Delta) Bcor (DeltaE9-10/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 (DeltaE9-10/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. |
