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
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Hematology, Endocrinology and Metabolism, Niigata University, Niigata, Japan.
J Exp Med. 2017 Oct 2;214(10):2901-2913. doi: 10.1084/jem.20170167. Epub 2017 Aug 21.
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.
在编码BCL6共抑制因子（BCOR）的X连锁基因中，已在多种血液系统恶性肿瘤中鉴定出复发性失活突变；然而，其肿瘤抑制功能在很大程度上仍未明确。我们构建了缺失外显子4的小鼠，其表达一种缺乏BCL6结合结构域的变异型BCOR。尽管雄性小鼠中外显子4的缺失损害了造血干细胞的再填充能力，但胸腺细胞在培养中有增强的增殖能力，并表现出强烈的诱导急性T细胞淋巴细胞白血病（T-ALL）的倾向，大多以Notch依赖的方式。T-ALL中的关键NOTCH1靶点之一在BCOR缺陷的T-ALL细胞中高度上调。染色质免疫沉淀/DNA测序分析表明，BCOR被招募到该启动子并在胸腺细胞中抑制其激活。BCOR还靶向其他NOTCH1靶点并可能拮抗它们的转录激活。BCOR缺陷的胸腺细胞表现出与Notch缺陷的胸腺细胞相似的行为。我们的结果首次证明了BCOR在T淋巴细胞恶性肿瘤发病机制中的肿瘤抑制作用。
