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    How FA proteins govern response of hematopoietic cells to physiological oxidative stress is an area of importance and yet has been studied only piecemeal, considering the oxidant hypersensitivity of FA BM cells.

    We will employ biochemical and genetic approaches to test the hypothesis that functional interaction between the FA proteins and other cell signaling pathways play important roles in maintaining normal hematopoiesis under physiologic oxidative stress, with specific focus on: 1) further characterizing the functional interaction between FANCD2 and the major oxidative stress-responsive transcription factor FOXO3a and 2) investigating the functional link between FA proteins and cellular anti-oxidant defense systems.

    New insights on the potential integration of the FA proteins in these oxidative-stress signaling pathways can suggest new targets for therapeutic prevention and treatment of bone marrow failure and cancer progression of the disease.

    FA is a genomic instability syndrome that is uniquely susceptible to physiologic oxidative stress, as patients accumulate abnormal levels of inflammatory ROS generated by overproduced TNF-. In FA inflammation-associated leukemogenesis, several non-mutually exclusive mechanisms may be involved, including defective DNA damage repair, impaired DNA damage response, and increased genomic instability.

    We hypothesize that increased ROS accumulation and vulnerability of the FA chromosomal DNA to oxidative damage would provide a genetic mechanism for FA genomic instability. We will employ two FA preleukemic models (FA patients at the MDS stage and the inflammation-induced Fancc-/- mouse preleukemic cells) to investigate the cellular mechanisms responsible for leukemic transformation in FA HSCs, with focus on the roles of FA proteins in oxidative DNA-damage response and repair, and the functional relationship between inflammatory ROS and genomic instability during FA leukemogenesis.  

    By demonstrating the link between inflammation and genomic instability, our study will challenge the current view of FA genomic instability being restricted to cross linker-induced DNA damage, with mechanistic implications for the health consequences of chronic inflammation particularly in the context of leukemogenesis.

    The mammalian DNA damage response (DDR) consists of a vast network of signal transduction cascades that amplify and relay the signal from DNA repair, cell cycle checkpoints and apoptosis pathways. These pathways are highly interconnected through complex nonlinear relationships, but how they function together at the systems level in the context of oxidative stress response is poorly understood.

    FA cells are defective in homologous recombination (HR) repair pathway and yet manage to survive double-strand DNA breaks (DSBs) generated by endogenous reactive oxygen species. We hypothesize that FA cells escape DSB-induced apoptosis via overuse of an alternative repair pathway during disease progression to leukemia. We will test this notion by investigating the potential synthetic lethal interactions between the FA pathway and other DNA repair pathways known to be involved in DDR, including HR, non-homologous end-joining (NHEJ), base excision repair (BER), nucleotide excision repair (NER) pathways.

    We expect that leukemic evolution in FA involves the addiction of HSC/P cells to a defined DNA repair pathway. Therefore, targeting the alternative, required repair pathway would improve FA leukemia therapy.

    We recently described cell-autonomous defects of FA HSC/P cells in BM homing and engraftment, and showed that these impaired functions were associated with a decrease in the activity of the Rho GTPase Cdc42 known to be essential for cell polarity, adhesion and migration. These results provide the first evidence for a missing link between FA deficiency and inefficient HSC engraftment. We hypothesize that cell-autonomous defect of FA HSC engraftment is a direct consequence of decreased Cdc42 activity, a property that could be utilized to vacant BM niche otherwise occupied by mutant HSC or leukemic stem cells (LSCs) and allow WT or gene-corrected HSC to engraft. The goals of the project are to demonstrate a proof of principle by targeting Cdc42 to (1) efficiently mobilize mutant HSCs or LSCs, (2) facilitate the engraftment of wild-type or gene-corrected HSCs in HSCT, and (3) improve stem cell and gene therapies for leukemia and BM failure diseases, clinical settings in which intensive preconditioning and scarce stem cell numbers critically limit success.


    The only curable treatment for FA is stem cell and gene therapies through hematopoietic stem cell transplantation (HSCT). However, three major hurdles that have been hampering scientific and clinical advance in the FA HSCT field. First, FA patients have extremely low number of HSCs. Moreover, FA hematopoietic stem cells (HSCs) show ineffective in mobilization. Second, FA patients are hypersensitive to key components of pre-conditioning regimens currently used in FA HSCT. Third, inefficient delivery of genetically corrected FA HSCs to the BM niche has impeded the goal of life long disease correction aimed by FA gene therapy. Therefore, there is a great need to develop novel pre-conditioning agents that can optimize homing and entry of HSCs into FA BM niche with minimal toxicity.

    The project will examine the competitiveness in engraftment potential of WT or FANCA-corrected HSCs in CASIN-conditioned Fanca-/- recipients. Further, an innovative FA xenotransplant model will be employed to address the efficacy of CASIN on engraftment of WT or genetically corrected FA patient HSCs.