在小鼠中同时敲除 Fancc 和 Fancg 基因可重现范可尼贫血的造血表现。
Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia.
机构信息
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
出版信息
Blood. 2010 Oct 21;116(16):2915-20. doi: 10.1182/blood-2009-08-240747. Epub 2010 Jul 6.
Abstract
Fanconi anemia (FA) is an inherited chromosomal instability syndrome characterized by bone marrow failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). Eight FA proteins associate in a nuclear core complex to monoubiquitinate FANCD2/FANCI in response to DNA damage. Additional functions have been described for some of the core complex proteins; however, in vivo genetic proof has been lacking. Here we show that double-mutant Fancc(-/-);Fancg(-/-) mice develop spontaneous hematologic sequelae including bone marrow failure, AML, MDS and complex random chromosomal abnormalities that the single-mutant mice do not. This genetic model provides evidence for unique core complex protein function independent of their ability to monoubiquitinate FANCD2/FANCI. Importantly, this model closely recapitulates the phenotypes found in FA patients and may be useful as a preclinical platform to evaluate the molecular pathogenesis of spontaneous bone marrow failure, MDS and AML in FA.
摘要
范可尼贫血症（FA）是一种遗传性染色体不稳定综合征，其特征为骨髓衰竭、骨髓增生异常（MDS）和急性髓系白血病（AML）。八种 FA 蛋白在核核心复合物中相互作用，以单泛素化 FANCD2/FANCI 作为对 DNA 损伤的响应。已经描述了一些核心复合物蛋白的其他功能；然而，缺乏体内遗传证据。在这里，我们表明双突变 Fancc(-/-);Fancg(-/-) 小鼠会自发出现血液学后遗症，包括骨髓衰竭、AML、MDS 和复杂的随机染色体异常，而单突变小鼠则不会。这种遗传模型为核心复合物蛋白的独特功能提供了证据，而与它们单泛素化 FANCD2/FANCI 的能力无关。重要的是，这种模型紧密地重现了在 FA 患者中发现的表型，并且可能作为一种临床前平台，用于评估 FA 中自发性骨髓衰竭、MDS 和 AML 的分子发病机制。
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