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Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2017-10-02 , DOI: 10.1084/jem.20170167
Tomoyuki Tanaka 1, 2 , Yaeko Nakajima-Takagi 1 , Kazumasa Aoyama 1 , Shiro Tara 1, 3 , Motohiko Oshima 1 , Atsunori Saraya 1 , Shuhei Koide 1 , Sha Si 1 , Ichiro Manabe 4 , Masashi Sanada 5 , Manabu Nakayama 6 , Masayoshi Masuko 7 , Hirohito Sone 2 , Haruhiko Koseki 8 , Atsushi Iwama 1
Affiliation  

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.



中文翻译:

BCOR的内部缺失揭示了T淋巴细胞恶性肿瘤中BCOR的抑癌功能

在X连锁的BCOR基因编码BCL6心脏抑制因子(BCOR)的各种血液系统恶性肿瘤中已经发现了反复失活的突变。然而,其肿瘤抑制功能仍未明确。我们生成了缺少Bcor外显子4的小鼠,该小鼠表达了缺少BCL6结合域的BCOR变异体。尽管雄性小鼠第4外显子的缺失(BcorΔE4 / y)损害了造血干细胞的繁殖能力,BcorΔE4/ y胸腺细胞具有增强的增殖能力,并具有诱导急性T细胞淋巴细胞白血病(T -ALL),大多数情况下取决于Notch。我的C在T-ALL临界NOTCH1目标之一,是高度在上调BCOR ΔE4/ Y T-ALL细胞。染色质免疫沉淀/ DNA测序分析表明BCOR被募集到Myc启动子并抑制其在胸腺细胞中的激活。BCOR还靶向其他NOTCH1靶标,并可能拮抗它们的转录激活。BCL6缺陷型胸腺细胞表现类似的方式BCOR ΔE4/ Y胸腺细胞。我们的研究结果提供了BCOR在T淋巴细胞恶性肿瘤发病机理中抑癌作用的第一个证据。

更新日期:2017-10-02
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