title: Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia.
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.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pulliam-Leath
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Ciccone
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Nalepa
authors.forename: Xiaxin
authors.initials: X
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Si
authors.forename: Leticia
authors.initials: L
authors.lastname: Miravalle
authors.forename: Danielle
authors.initials: D
authors.lastname: Smith
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: Jingling
authors.initials: J
authors.lastname: Li
authors.forename: Praveen
authors.initials: P
authors.lastname: Anur
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.forename: Gail H
authors.initials: GH
authors.lastname: Vance
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000503:physiopathology*; D002869:Chromosome Aberrations; D005199:Fanconi Anemia / Q000235:genetics*; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics*; D052241:Fanconi Anemia Complementation Group G Protein / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*
chemical_list: C497652:Fancc protein, mouse; C499910:Fancg protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D052241:Fanconi Anemia Complementation Group G Protein