Fanconi anemia (FA) is a complex, autosomal recessive disorder characterized by bone marrow (BM) failure, increased incidence of malignancies, and hypersensitivity to bifunctional alkylating agents such as mitomycin C (MMC). There are eight complementation types of FA that have overlapping phenotypes inferring the existence of eight genes in a common biochemical pathway. It is clear that the hematopoietic progenitor compartment is affected by loss of Fanconi anemia complementation type C protein (FAC). However, no direct studies have been conducted evaluate whether the hematopoietic stem cell (HSC) compartment is similarly affected due to difficulties in assessing HSC function in the human system. The development of a murine model containing a homozygous disruption in the murine homologue (Fac) of FAC allows comprehensive evaluation of this question. Using this murine model, we showed that Fac -/- hematopoietic progenitors were hypersensitive to MMC, similar to FA patients. These data suggest that Fac -/- mice will be a good model system to study FA. Several lines of evidence suggest that FA proteins may have a role in maintaining normal oxidative metabolism. In addition, the recent observation in COS cells that FAC modulates NADPH:cytochrome p450 reductase (RED) activity, an important enzyme that generates oxygen radicals and activates several drugs such as MMC supports this hypothesis. The goals of this application are: 1) to determine whether loss of Fac affects HSC function, 2) to determine if Fac -/- hematopoietic cells have an increased sensitivity to oxidative stress, and 3) to evaluate whether overexpression of RED induces a hypersensitivity to oxidative stresss in Fac +/+ cells. These data will provide important information in elucidating the pathogenesis of BM failure and carcinogenesis in FA as well as investigate a distinct function of Fac in normal oxidative metabolism that could provide potential implications for modifying current treatment protocols for FA patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL004071-03
Application #
6388557
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M1))
Program Officer
Werner, Ellen
Project Start
1999-08-13
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$121,766
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Saadatzadeh, M Reza; Bijangi-Vishehsaraei, Khadijeh; Hong, Ping et al. (2004) Oxidant hypersensitivity of Fanconi anemia type C-deficient cells is dependent on a redox-regulated apoptotic pathway. J Biol Chem 279:16805-12
Haneline, Laura S; Li, Xiaxin; Ciccone, Samantha L M et al. (2003) Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc-/- hematopoietic stem cells and decreases the risk of clonal evolution. Blood 101:1299-307
Li, Xiaxin; Plett, P Artur; Yang, Yanzhu et al. (2003) Fanconi anemia type C-deficient hematopoietic stem/progenitor cells exhibit aberrant cell cycle control. Blood 102:2081-4
Freie, Brian; Li, Xiaxin; Ciccone, Samantha L M et al. (2003) Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. Blood 102:4146-52