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

Anna C. Pulliam-Leath, Samantha L. Ciccone, Grzegorz Nalepa, Xiaxin Li, Yue Si, Leticia Miravalle, Danielle Smith, Jin Yuan, Jingling Li, Praveen Anur, Attilio Orazi, Gail H. Vance, Feng Chun Yang, Helmut Hanenberg, Grover C. Bagby, D. Wade Clapp

Research output: Contribution to journalArticle

31 Scopus citations

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 singlemutant 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.

Original languageEnglish (US)
Pages (from-to)2915-2920
Number of pages6
JournalBlood
Volume116
Issue number16
DOIs
StatePublished - Oct 21 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Pulliam-Leath, A. C., Ciccone, S. L., Nalepa, G., Li, X., Si, Y., Miravalle, L., Smith, D., Yuan, J., Li, J., Anur, P., Orazi, A., Vance, G. H., Yang, F. C., Hanenberg, H., Bagby, G. C., & Clapp, D. W. (2010). Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia. Blood, 116(16), 2915-2920. https://doi.org/10.1182/blood-2009-08-240747