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

Abstract

Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked <i>BCOR</i> gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing <i>Bcor</i> exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (<i>Bcor^ΔE4/y</i> ) compromised the repopulating capacity of hematopoietic stem cells, <i>Bcor^ΔE4/y</i> 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. <i>Myc</i>, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in <i>Bcor^ΔE4/y</i> T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the <i>Myc</i> promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. <i>Bcl6</i>-deficient thymocytes behaved in a manner similar to <i>Bcor^ΔE4/y</i> thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.