Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia.
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.
Pulliam-Leath
Anna C
AC
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Ciccone
Samantha L
SL
Nalepa
Grzegorz
G
Li
Xiaxin
X
Si
Yue
Y
Miravalle
Leticia
L
Smith
Danielle
D
Yuan
Jin
J
Li
Jingling
J
Anur
Praveen
P
Orazi
Attilio
A
Vance
Gail H
GH
Yang
Feng-Chun
FC
Hanenberg
Helmut
H
Bagby
Grover C
GC
Clapp
D Wade
DW
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*
C497652:Fancc protein, mouse; C499910:Fancg protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D052241:Fanconi Anemia Complementation Group G Protein