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

J Exp Med. 2017 Oct 2;214(10):2901-2913. doi: 10.1084/jem.20170167. Epub 2017 Aug 21.


Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (BcorΔE4/y ) compromised the repopulating capacity of hematopoietic stem cells, BcorΔE4/y 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. Myc, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in BcorΔE4/y T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the Myc promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. Bcl6-deficient thymocytes behaved in a manner similar to BcorΔE4/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.

MeSH terms

  • Animals
  • Exons
  • Flow Cytometry
  • Gene Deletion
  • Hematopoietic Stem Cells / metabolism
  • Male
  • Mice
  • Mice, Mutant Strains
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1 / metabolism
  • Repressor Proteins / physiology*
  • Thymocytes / metabolism
  • Tumor Suppressor Proteins / physiology*


  • Bcor protein, mouse
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Repressor Proteins
  • Tumor Suppressor Proteins