Continuous in vivo infusion of interferon-gamma (IFN-gamma) enhances engraftment of syngeneic wild-type cells in Fanca-/- and Fancg-/- mice.
Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of 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. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc-/- cells to interferon-gamma (IFN-gamma), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc-/- mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca-/- and Fancg-/- mice are hypersensitive to IFN-gamma and that in vivo infusion of IFN-gamma at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-gamma conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients.
Si
Yue
Y
Department of Microbiology and Immunology, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, USA.
Ciccone
Samantha
S
Yang
Feng-Chun
FC
Yuan
Jin
J
Zeng
Daisy
D
Chen
Shi
S
van de Vrugt
Henri J
HJ
Critser
John
J
Arwert
Fre
F
Haneline
Laura S
LS
Clapp
D Wade
DW
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D005199:Fanconi Anemia / Q000235:genetics / Q000628:therapy*; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics*; D052241:Fanconi Anemia Complementation Group G Protein / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000637:transplantation*; D014161:Transduction, Genetic / Q000379:methods; D014182:Transplantation, Autologous; D014185:Transplantation, Isogeneic
D000998:Antiviral Agents; C120277:Fanca protein, mouse; C499910:Fancg protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052241:Fanconi Anemia Complementation Group G Protein; D007371:Interferon-gamma