Fanconi anemia type C-deficient hematopoietic stem/progenitor cells exhibit aberrant cell cycle control.
The pathogenesis of bone marrow failure in Fanconi anemia is poorly understood. Suggested mechanisms include enhanced apoptosis secondary to DNA damage and altered inhibitory cytokine signaling. Recent data determined that disrupted cell cycle control of hematopoietic stem and/or progenitor cells disrupts normal hematopoiesis with increased hematopoietic stem cell cycling resulting in diminished function and increased sensitivity to cell cycle-specific apoptotic stimuli. Here, we used Fanconi anemia complementation type C-deficient (Fancc-/-) mice to demonstrate that Fancc-/- phenotypically defined cell populations enriched for hematopoietic stem and progenitor cells exhibit increased cycling. In addition, we established that the defect in cell cycle regulation is not a compensatory mechanism from enhanced apoptosis occurring in vivo. Collectively, these data provide a previously unrecognized phenotype in Fancc-/- hematopoietic stem/progenitor cells, which may contribute to the progressive bone marrow failure in Fanconi anemia.
Li
Xiaxin
X
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202-5254.
Plett
P Artur
PA
Yang
Yanzhu
Y
Hong
Ping
P
Freie
Brian
B
Srour
Edward F
EF
Orschell
Christie M
CM
Clapp
D Wade
DW
Haneline
Laura S
LS
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001853:Bone Marrow / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins; D010641:Phenotype; D011506:Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins