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

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626398/
https://www.ncbi.nlm.nih.gov/pubmed/28827447
http://dx.doi.org/10.1084/jem.20170167
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author 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
author_facet 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
author_sort Tanaka, Tomoyuki
collection PubMed
description 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(ΔE4/y)) compromised the repopulating capacity of hematopoietic stem cells, Bcor(ΔE4/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(ΔE4/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(ΔE4/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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spelling pubmed-56263982018-04-02 Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies 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 J Exp Med Research Articles 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(ΔE4/y)) compromised the repopulating capacity of hematopoietic stem cells, Bcor(ΔE4/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(ΔE4/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(ΔE4/y) thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies. The Rockefeller University Press 2017-10-02 /pmc/articles/PMC5626398/ /pubmed/28827447 http://dx.doi.org/10.1084/jem.20170167 Text en © 2017 Tanaka et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
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
Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies
title Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies
title_full Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies
title_fullStr Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies
title_full_unstemmed Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies
title_short Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies
title_sort internal deletion of bcor reveals a tumor suppressor function for bcor in t lymphocyte malignancies
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626398/
https://www.ncbi.nlm.nih.gov/pubmed/28827447
http://dx.doi.org/10.1084/jem.20170167
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