Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Blood. 2010 Oct 21;116(16):2915-20. doi: 10.1182/blood-2009-08-240747. Epub 2010 Jul 6.
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.
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。
