Continuous in vivo infusion of interferon-gamma (IFN-gamma) preferentially reduces myeloid progenitor numbers and enhances engraftment of syngeneic wild-type cells in Fancc-/- mice.
Fanconi anemia (FA) is characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of many FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. Previous studies in FA murine models and in a phase 1 clinical trial suggest that myelopreparation is required for significant engraftment of exogenous, genetically corrected stem cells. Since myeloid progenitors from Fancc-/- mice and human Fanconi anemia group C protein (FANCC) patients have increased apoptosis in response to interferon gamma (IFN-gamma) in vitro, we hypothesized that IFN-gamma may be useful as a nongenotoxic, myelopreparative conditioning agent. To test this hypothesis, IFN-gamma was administered as a continuous infusion to Fancc-/- and wild-type (WT) mice for 1 week. Primitive and mature myeloid lineages were preferentially reduced in IFN-gamma-treated Fancc-/- mice. Further, IFN-gamma conditioning of Fancc-/- recipients was sufficient as a myelopreparative regimen to allow consistent engraftment of isogenic WT repopulating stem cells. Collectively, these data demonstrate that Fancc-/- hematopoietic cell populations have increased hypersensitivity to IFN-gamma in vivo and that IFN-gamma conditioning may be useful as a nongenotoxic strategy for myelopreparation in this disorder.
Li
Xiaxin
X
Indiana University School of Medicine, Herman B. Wells Center for Pediatric Research, Cancer Research Institute, 1044 W Walnut St, Rm 402,Indianapolis, IN 46202-5254, USA.
Yang
Yanzhu
Y
Yuan
Jin
J
Hong
Ping
P
Freie
Brian
B
Orazi
Attilio
A
Haneline
Laura S
LS
Clapp
D Wade
DW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000379:methods; D002452:Cell Count; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000172:deficiency*; D005199:Fanconi Anemia / Q000188:drug therapy* / Q000628:therapy; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006085:Graft Survival / Q000187:drug effects*; D007263:Infusions, Parenteral; D007371:Interferon-gamma / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects; D023461:Myeloid Progenitor Cells / Q000187:drug effects*; D009687:Nuclear Proteins / Q000172:deficiency*; D019172:Transplantation Conditioning / Q000379:methods; D014185:Transplantation, Isogeneic
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; D007371:Interferon-gamma