2017 Fiscal Year Final Research Report
Tumor suppressor role of BCOR in hematopoiesis
Project/Area Number |
16K15498
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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Allocation Type | Multi-year Fund |
Research Field |
Hematology
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Research Institution | Chiba University |
Principal Investigator |
Iwama Atsushi 千葉大学, 大学院医学研究院, 教授 (70244126)
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Project Period (FY) |
2016-04-01 – 2018-03-31
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Keywords | BCOR / がん抑制遺伝子 / 造血腫瘍 |
Outline of Final Research Achievements |
Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR). We herein generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain (BcorΔE4/y). 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 upregulated in BcorΔE4/y T-ALL cells. ChIP-seq 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 similar manner to BcorΔE4/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.
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Free Research Field |
血液内科学
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