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

• Published in: The Journal of experimental medicine 2017-10, Vol.214 (10), p.2901-2913
• Main Authors: Tanaka, Tomoyuki, Nakajima-Takagi, Yaeko, Aoyama, Kazumasa, Tara, Shiro, Oshima, Motohiko, Saraya, Atsunori, Koide, Shuhei, Si, Sha, Manabe, Ichiro, Sanada, Masashi, Nakayama, Manabu, Masuko, Masayoshi, Sone, Hirohito, Koseki, Haruhiko, Iwama, Atsushi
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Animals; Bcl-6 protein; Binding; Cell culture; Chromatin; Clonal deletion; Deoxyribonucleic acid; DNA; DNA sequencing; Exons; Flow Cytometry; Gene Deletion; Hematology; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Immunoprecipitation; Leukemia; Lymphatic leukemia; Lymphocytes T; Male; Mice; Mice, Mutant Strains; Mutation; Myc protein; Notch1 protein; Pathogenesis; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Real-Time Polymerase Chain Reaction; Receptor, Notch1 - metabolism; Repressor Proteins - physiology; Rodents; Stem cell transplantation; Stem cells; Thymocytes; Thymocytes - metabolism; Transcription activation; Tumor suppressor genes; Tumor Suppressor Proteins - physiology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20170167

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.