TY - JOUR
T1 - Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia
AU - Pulliam-Leath, Anna C.
AU - Ciccone, Samantha L.
AU - Nalepa, Grzegorz
AU - Li, Xiaxin
AU - Si, Yue
AU - Miravalle, Leticia
AU - Smith, Danielle
AU - Yuan, Jin
AU - Li, Jingling
AU - Anur, Praveen
AU - Orazi, Attilio
AU - Vance, Gail H.
AU - Yang, Feng Chun
AU - Hanenberg, Helmut
AU - Bagby, Grover C.
AU - Clapp, D. Wade
PY - 2010/10/21
Y1 - 2010/10/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77958190427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77958190427&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-08-240747
DO - 10.1182/blood-2009-08-240747
M3 - Article
C2 - 20606166
AN - SCOPUS:77958190427
SN - 0006-4971
VL - 116
SP - 2915
EP - 2920
JO - Blood
JF - Blood
IS - 16
ER -