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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 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 (Bcor?E4/y ) compromised the repopulating capacity of hematopoietic stem cells, Bcor?E4/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 Bcor?E4/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 Bcor?E4/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.

SUBMITTER: Tanaka T

PROVIDER: S-EPMC5626398 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Tanaka Tomoyuki T Nakajima-Takagi Yaeko Y Aoyama Kazumasa K Tara Shiro S Oshima Motohiko M Saraya Atsunori A Koide Shuhei S Si Sha S Manabe Ichiro I Sanada Masashi M Nakayama Manabu M Masuko Masayoshi M Sone Hirohito H Koseki Haruhiko H Iwama Atsushi A

The Journal of experimental medicine 20170821 10

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</su ...[more]

PMID: 28827447

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Project description:BACKGROUND:Extracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered tumor cell metabolism. Acidosis has pleiotropic effects on malignant progression; therefore it is essential to understand how acidosis exerts its diverse effects. TDAG8 is a proton-sensing G-protein-coupled receptor that can be activated by extracellular acidosis. METHODS:TDAG8 gene expression was analyzed by bioinformatic analyses and quantitative RT-PCR in human hematological malignancies. Retroviral transduction was used to restore TDAG8 expression in U937, Ramos and other blood cancer cells. Multiple in vitro and in vivo tumorigenesis and metastasis assays were employed to evaluate the effects of TDAG8 expression on blood cancer progression. Western blotting, immunohistochemistry and biochemical approaches were applied to elucidate the underlying mechanisms associated with the TDAG8 receptor pathway. RESULTS:TDAG8 expression is significantly reduced in human blood cancers in comparison to normal blood cells. Severe acidosis, pH 6.4, inhibited U937 cancer cell proliferation while mild acidosis, pH 6.9, stimulated its proliferation. However, restoring TDAG8 gene expression modulated the U937 cell response to mild extracellular acidosis and physiological pH by reducing cell proliferation. Tumor xenograft experiments further revealed that restoring TDAG8 expression in U937 and Ramos cancer cells reduced tumor growth. It was also shown U937 cells with restored TDAG8 expression attached less to Matrigel, migrated slower toward a chemoattractant, and metastasized less in severe combined immunodeficient mice. These effects correlated with a reduction in c-myc oncogene expression. The mechanistic investigation indicated that G?13/Rho signaling arbitrated the TDAG8-mediated c-myc oncogene repression in response to acidosis. CONCLUSIONS:This study provides data to support the concept that TDAG8 functions as a contextual tumor suppressor down-regulated in hematological malignancies and potentiation of the TDAG8 receptor pathway may be explored as a potential anti-tumorigenic approach in blood cancers.

Dataset Information

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

Publications

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

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