Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia
Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia
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DOI：
10.1182/blood-2009-08-240747
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发表时间：
2010-10-21
期刊：
影响因子：
20.3
通讯作者：
Clapp, D. Wade
中科院分区：
文献类型：
--
作者：
Pulliam-Leath, Anna C.;Ciccone, Samantha L.;Clapp, D. Wade
范可尼贫血（FA）是一种遗传性染色体不稳定综合征，以骨髓衰竭、骨髓增生异常（MDS）和急性髓性白血病（AML）为特征。8个FA蛋白结合在一个核核心复合体中，对DNA损伤作出单泛素化FANCD2/FANCI的反应。一些核心复合物蛋白的附加功能已被描述；然而，缺乏体内遗传证据。这里我们展示了双突变的Fancc(-/-)；fang（-/-）小鼠会出现自发性血液学后遗症，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。该遗传模型提供了独特的核心复合蛋白功能独立于其单泛素化FANCD2/FANCI的能力的证据。重要的是，该模型密切概括了FA患者的表型，可能有助于作为临床前平台来评估FA患者自发性骨髓衰竭、MDS和AML的分子发病机制。(Blood.2010; 116 (16): 2915 - 2920)
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. (Blood.2010;116(16):2915-2920)