Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice
Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice
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DOI：
10.1073/pnas.250492697
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发表时间：
2000-12-05
影响因子：
11.1
通讯作者：
Orkin, SH
中科院分区：
文献类型：
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作者：
Roberts, CWM;Galusha, SA;Orkin, SH
恶性横纹肌样瘤（MRT）是一种侵袭性强、致死率高的儿童恶性肿瘤。肿瘤发生在不同的位置，包括肾脏，大脑和软组织。尽管进行了强化治疗，但80%的受影响儿童通常在诊断后1年内死亡。大多数MRT样品和细胞系具有持续的hSNF 5（整合酶相互作用因子1）基因的双等位基因失活突变，表明hSNF 5可充当肿瘤抑制因子。我们试图在小鼠模型中研究Snf 5在发育和癌症中的作用。在这里，我们报告说，Snf 5是广泛表达的胚胎发育过程中的高水平表达的第一鳃弓和中枢神经系统的下颌部分的焦点领域。纯合子敲除Snf 5导致胚胎第7天的胚胎死亡，而杂合子小鼠以预期的频率出生并表现正常。然而，早在5周龄开始，杂合子小鼠发展肿瘤与MRT一致，大多数肿瘤发生在软组织中来自第一鳃弓。我们的研究结果构成了有说服力的遗传证据表明，Snf 5，Swi/Snf染色质重塑复合物的核心成员，作为肿瘤抑制基因的功能，而且，Snf 5杂合子提供了这种致命的儿科癌症的小鼠模型。
Malignant rhabdoid tumor (MRT) is an aggressive, highly lethal cancer of young children. Tumors occur in various locations, including kidney, brain, and soft tissues. Despite intensive therapy, 80% of affected children die, often within 1 year of diagnosis. The majority of MRT samples and cell lines have sustained biallelic inactivating mutations of the hSNF5 (integrase interactor 1) gene, suggesting that hSNF5 may act as a tumor suppressor. We sought to examine the role of Snf5 in development and cancer in a murine model. Here we report that Snf5 is widely expressed during embryogenesis with focal areas of high-level expression in the mandibular portion of the first branchial arch and central nervous system. Homozygous knockout of Snf5 results in embryonic lethality by embryonic day 7, whereas heterozygous mice are born at the expected frequency and appear normal. However, beginning as early as 5 weeks of age, heterozygous mice develop tumors consistent with MRT, The majority of tumors arise in soft tissues derived from the first branchial arch. Our findings constitute persuasive genetic evidence that Snf5, a core member of the Swi/Snf chromatin-remodeling complex, functions as a tumor suppressor gene, and, moreover, Snf5 heterozygotes provide a murine model of this lethal pediatric cancer.