Fanconi's Anemia (FA) is a genetic disorder manifesting with typical congenital malformations, childhood onset progressive bone marrow failure and increased cancer risk. 13 genes responsible for FA have been cloned and together constitute the FA/BRCA pathway which functions to maintain genome stability and to ensure stem cell survival. This Program Project will use a multidisciplinary approach to dissecting the molecular pathophysiology of FA and to use this knowledge to enhance therapy for FA, especially small molecule intervention. The clinical disciplines represented by the investigators include pediatrics, medical genetics, hematology and oncology. The scientific areas of expertise include stem cell biology, DNA repair, molecular hematology, zebra fish genetics, mouse genetics, cytogenetics, gene therapy and drug discovery. Core A will use cell-based assays to screen for novel compounds and genes that positively impact the phenotypes of FA cells. New drugs discovered by screening and others derived from insights into pathophysiology will be systematically evaluated in all 3 projects. Project 1 uses zebrafish models of FA, projects 2 and 3 use FA knockout mice as well as pluripotent stem cells from human FA patients. These IPS cells generated by direct reprogramming will be provided by Core C. Cytogenetic abnormalities are a key feature of FA and Core B will provide support in this area. In addition to drug screening the projects will study genetic interactions of the FA/BRCA pathway, work on the non-canonical roles of FA proteins and explore gene repair as a novel approach for gene therapy in the disease.

Public Health Relevance

The significance of this Program Project is multifold in that therapeutic benefits for FA patients are likely. In addition, however, the work will shed light on generally important processes such as the maintenance of hematopoietic stem cells in the face of damage, leukemogenesis and the action of synthetic androgens in stem cells. Furthermore, drugs that benefit bone marrow failure and delay cancer in FA may well useful in other forms of aplastic anemia and cancer.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Qasba, Pankaj
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Oregon Health and Science University
Schools of Medicine
United States
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Garbati, Michael R; Hays, Laura E; Rathbun, R Keaney et al. (2016) Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages. J Leukoc Biol 99:455-65
Zhang, Haojian; Kozono, David E; O'Connor, Kevin W et al. (2016) TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia. Cell Stem Cell 18:668-81
Lombardi, Anne J; Hoskins, Elizabeth E; Foglesong, Grant D et al. (2015) Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers. Clin Cancer Res 21:1962-72
Xie, Jenny; Kim, Hyungjin; Moreau, Lisa A et al. (2015) RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway. J Clin Invest 125:1523-32
Zhang, Qing-Shuo; Deater, Matthew; Schubert, Kathryn et al. (2015) The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. Stem Cell Res 15:130-40
Zhang, Qing-Shuo; Benedetti, Eric; Deater, Matthew et al. (2015) Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. Stem Cell Reports 4:90-102
Zhang, Qing-Shuo; Marquez-Loza, Laura; Sheehan, Andrea M et al. (2014) Evaluation of resveratrol and N-acetylcysteine for cancer chemoprevention in a Fanconi anemia murine model. Pediatr Blood Cancer 61:740-2
Kim, Hyungjin; Dejsuphong, Donniphat; Adelmant, Guillaume et al. (2014) Transcriptional repressor ZBTB1 promotes chromatin remodeling and translesion DNA synthesis. Mol Cell 54:107-18
Fargo, John H; Rochowski, Andrzej; Giri, Neelam et al. (2014) Comparison of chromosome breakage in non-mosaic and mosaic patients with Fanconi anemia, relatives, and patients with other inherited bone marrow failure syndromes. Cytogenet Genome Res 144:15-27
Owen, Nichole; Hejna, James; Rennie, Scott et al. (2014) Bloom syndrome radials are predominantly non-homologous and are suppressed by phosphorylated BLM. Cytogenet Genome Res 144:255-63

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