title: Loss of FancC function results in decreased hematopoietic stem cell repopulating ability.
abstract: Fanconi anemia (FA) is a complex genetic disorder characterized by progressive bone marrow (BM) aplasia, chromosomal instability, and acquisition of malignancies, particularly myeloid leukemia. We used a murine model containing a disruption of the murine homologue of FANCC (FancC) to evaluate short- and long-term multilineage repopulating ability of FancC -/- cells in vivo. Competitive repopulation assays were conducted where "test" FancC -/- or FancC +/+ BM cells (expressing CD45.2) were cotransplanted with congenic competitor cells (expressing CD45.1) into irradiated mice. In two independent experiments, we determined that FancC -/- BM cells have a profound decrease in short-term, as well as long-term, multilineage repopulating ability. To determine quantitatively the relative production of progeny cells by each test cell population, we calculated test cell contribution to chimerism as compared with 1 x 10(5) competitor cells. We determined that FancC -/- cells have a 7-fold to 12-fold decrease in repopulating ability compared with FancC +/+ cells. These data indicate that loss of FancC function results in reduced in vivo repopulating ability of pluripotential hematopoietic stem cells, which may play a role in the development of the BM failure in FA patients. This model system provides a powerful tool for evaluation of experimental therapeutics on hematopoietic stem cell function.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Haneline
authors.forename: T A
authors.initials: TA
authors.lastname: Gobbett
authors.forename: R
authors.initials: R
authors.lastname: Ramani
authors.forename: M
authors.initials: M
authors.lastname: Carreau
authors.forename: M
authors.initials: M
authors.lastname: Buchwald
authors.forename: M C
authors.initials: MC
authors.lastname: Yoder
authors.forename: D W
authors.initials: DW
authors.lastname: Clapp
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000502:physiology; D051379:Mice; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics*
chemical_list: 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