Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies.

Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice ( ) compromised the repopulating capacity of hematopoietic stem cells, thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. , one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. -deficient thymocytes behaved in a manner similar to thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.