Disrupting Bcor binding to Bcl6 unveils a tumor suppressor function of Bcor in T lymphocyte malignancies

Recurrent inactivating mutations have been identified in the X-linked BCOR gene encoding BCL6 corepressor (BCOR) in various hematological malignancies. However, its tumor suppressor function remains uncharacterized. Here, we generated mice lacking Bcor exon 4, expressing a variant Bcor lacking Bcl6-binding domain. While deletion of exon 4 in male mice (Bcor-deltaE4/y) compromised repopulating capacity of hematopoietic stem cells, Bcor-deltaE4/y thymocytes had an augmented proliferative capacity in culture and showed a strong propensity to induce lethal acute T-cell lymphoblastic leukemia (T-ALL). c-Myc, one of the critical Notch1 targets in T-ALL, was highly activated in Bcor-delta/y T-ALL cells. ChIP sequence analysis revealed that Bcor is recruited to the c-Myc promoter and restrains its activation in thymocytes. Bcor also targets other Notch1 targets and potentially antagonizes their transcriptional activation. Bcl6-deficient thymocytes behaved in a manner similar to Bcor-deltaE4/y thymocytes. Our findings provide the first evidence of a tumor suppressor role of Bcor via its corepressor function of Bcl6 in the pathogenesis of hematological malignancies.