Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms
Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms
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DOI：
10.1038/ng.2731
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发表时间：
2013-10-01
期刊：
影响因子：
30.8
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
--
作者：
Kon, Ayana;Shih, Lee-Yung;Ogawa, Seishi
黏连蛋白是一种多聚体蛋白复合物，参与姐妹染色单体的黏连、复制后DNA修复和转录调控。在这里，我们报告复发性突变和缺失，涉及多个组成部分的凝聚素复合物，包括STAG 2，RAD 21，SMC 1A和SMC 3，在不同的骨髓肿瘤。这些突变和缺失大多是相互排斥的，发生在12.1%（19/157）的急性髓系白血病，8.0%（18/224）的骨髓增生异常综合征，10.2%（9/88）的慢性粒单核细胞白血病，6.3%（4/64）的慢性粒细胞白血病和1.3%（1/77）的经典骨髓增生性肿瘤。粘着蛋白突变的白血病细胞显示染色质结合的粘着蛋白成分的量减少，这表明染色质上的粘着蛋白结合位点的大量损失。通过分别强制表达野生型RAD 21和野生型RAD 21和STAG 2，抑制了在RAD 21中具有突变的白血病细胞系（Kasumi-1细胞）或具有严重降低的RAD 21和STAG 2表达的白血病细胞系（MOLM-13细胞）的生长。这些发现表明，在髓系白血病发生中，粘附素功能受损发挥作用。
Cohesin is a multimeric protein complex that is involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Here we report recurrent mutations and deletions involving multiple components of the cohesin complex, including STAG2, RAD21, SMC1A and SMC3, in different myeloid neoplasms. These mutations and deletions were mostly mutually exclusive and occurred in 12.1% (19/157) of acute myeloid leukemia, 8.0% (18/224) of myelodysplastic syndromes, 10.2% (9/88) of chronic myelomonocytic leukemia, 6.3% (4/64) of chronic myelogenous leukemia and 1.3% (1/77) of classical myeloproliferative neoplasms. Cohesin-mutated leukemic cells showed reduced amounts of chromatin-bound cohesin components, suggesting a substantial loss of cohesin binding sites on chromatin. The growth of leukemic cell lines harboring a mutation in RAD21 (Kasumi-1 cells) or having severely reduced expression of RAD21 and STAG2 (MOLM-13 cells) was suppressed by forced expression of wild-type RAD21 and wild-type RAD21 and STAG2, respectively. These findings suggest a role for compromised cohesin functions in myeloid leukemogenesis.