Fanca-/- hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766.
Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca(-/-) mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca(-/-) hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia.
Milsom
Michael D
MD
Division of Experimental Hematology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
Lee
Andrew W
AW
Zheng
Yi
Y
Cancelas
Jose A
JA
D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics* / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D013234:Stem Cells; D020744:rac GTP-Binding Proteins / Q000009:adverse effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000634:Aminoquinolines; C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; C487513:NSC 23766; D011743:Pyrimidines; D016179:Granulocyte Colony-Stimulating Factor; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins