Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia

• Published in: Blood Vol. 116; no. 16; pp. 2915 - 2920
• Main Authors: Pulliam-Leath, Anna C., Ciccone, Samantha L., Nalepa, Grzegorz, Li, Xiaxin, Si, Yue, Miravalle, Leticia, Smith, Danielle, Yuan, Jin, Li, Jingling, Anur, Praveen, Orazi, Attilio, Vance, Gail H., Yang, Feng-Chun, Hanenberg, Helmut, Bagby, Grover C., Clapp, D. Wade
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 21-10-2010; Americain Society of Hematology; American Society of Hematology
• Series: Hematopoiesis and Stem Cells
• Subjects: Anemias. Hemoglobinopathies; Animals; Biological and medical sciences; Bone Marrow - physiopathology; Chromosome Aberrations; Diseases of red blood cells; Fanconi Anemia - genetics; Fanconi Anemia Complementation Group C Protein - genetics; Fanconi Anemia Complementation Group G Protein - genetics; Hematologic and hematopoietic diseases; Hematopoiesis and Stem Cells; Leukemia, Myeloid, Acute - genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mutation; Myelodysplastic Syndromes - genetics; Chromosome fragility; Fanconi anemia; Hematology; Rodentia; Hemopathy; Genetic disease; Vertebrata; Mammalia; Mouse; Animal; Genetics; Anemia Fanconi group G; Anemia Fanconi group C
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-08-240747

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.