Roberts C W, Galusha S A, McMenamin M E, Fletcher C D, Orkin S H
Division of Hematology-Oncology, Children's Hospital and Dana Farber Cancer Institute, Department of Pediatrics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13796-800. doi: 10.1073/pnas.250492697.
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.
恶性横纹肌样瘤（MRT）是一种侵袭性强、致死率高的幼儿癌症。肿瘤发生于多个部位，包括肾脏、大脑和软组织。尽管进行了强化治疗，80%的患病儿童仍会死亡，通常在确诊后1年内。大多数MRT样本和细胞系存在hSNF5（整合酶相互作用因子1）基因的双等位基因失活突变，这表明hSNF5可能作为一种肿瘤抑制因子发挥作用。我们试图在小鼠模型中研究Snf5在发育和癌症中的作用。在此我们报告，Snf5在胚胎发育过程中广泛表达，在第一鳃弓的下颌部分和中枢神经系统有高水平表达的局部区域。Snf5的纯合敲除导致胚胎在第7天死亡，而杂合小鼠以预期频率出生且外观正常。然而，早在5周龄时，杂合小鼠就会发生与MRT一致的肿瘤。大多数肿瘤发生在源自第一鳃弓的软组织中。我们的研究结果构成了有说服力的遗传学证据，表明Swi/Snf染色质重塑复合物的核心成员Snf5作为肿瘤抑制基因发挥作用，此外，Snf5杂合子提供了这种致死性儿科癌症的小鼠模型。
