In our research projects, we utilize cellular, genetic and molecular techniques to identify and characterize critical pathways that regulate hematopoietic stem cell functions using knockout (KO) mice and xenotransplant models.
My laboratory focuses on elucidating the mechanisms by which the Fanconi anemia (FA) proteins regulate hematopoietic stem cells in the context of bone marrow failure (BMF) and leukemia development. The goal of my research is to identify novel pharmaceutical targets for the treatment of patients with FA and other bone marrow failure syndromes (BMFS).
The process of FA disease progression in the context of hematopoiesis is characterized by bone marrow failure, clonal proliferation of hematopoietic stem (HSC) and progenitor (P) cells, and progression to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The only curable treatment for this devastating disease is stem cell therapy through bone marrow transplantation.
My early work focused on the role of inflammation in the biology of HSCs and leukemic evolution in FA, an inherited BMFS. These studies were published in the Journal of Clinical Investigation in 2007.
I made three contributions to our understanding of FA disease progression. First, I identified IL-3Rα as a unique cell-surface marker for leukemia-initiating cells in FA AML. This finding lays the groundwork for studying leukemic evolution in FA and may lead to a new avenue of research designed to target these leukemia-initiating cells for developing innovative treatments for FA BMF and leukemia. Second, I established a functional link between abnormal HSC differentiation and disease progression in FA. This study identified functional crosstalk between the NF-kB pathway and Notch signaling in HSC differentiation and improved the understanding of the pathogenesis of BMF and leukemia in FA. Third, I reported for the first time that deletion of the FA core complex gene Fanca or Fancd2 in mice dysregulated the suppressive activity of regulatory Tregs cells (T cells), leading to exacerbated graft-vs-host disease (GVHD) in mice. This novel GVHD experimental system mimics the clinical setting of FA allogeneic stem cell transplantation. It may serve as a unique model for studying the pathophysiology of FA GVHD.
I’ve devoted much effort to the study on the functional interaction between the FA deoxyribonucleic acid (DNA) repair pathway and other cellular defense systems in preventing oxidative damage-induced hematopoietic defects. As the primary investigator or co-investigator, I demonstrated the functional interaction between the FA DNA repair pathway and the forkhead box O3 (FOXO3a) antioxidant defense pathway as well as the poly (ADP-ribose) polymerase (PARP) -1 repair pathway in preventing oxidative DNA damage in hematopoietic cells. These studies document the contribution of these novel interactions between different repair pathways to cellular antioxidant defense. They also suggest new targets for therapeutically exploring the pathogenic role of oxidative stress in hematologic diseases.
I have explored the hypothesis of targeting the FA DNA repair pathway in cancer therapy. Since mutation or silencing of genes controlling the FA pathway has been linked to increased drug sensitivity, I proposed that inhibition of the FA pathway combined with DNA damaging anti-cancer drugs might represent a promising strategy for cancer therapy.
Along with a team of collaborators, I used a conditional mammalian target of rapamycin (mTOR) KO mouse model to demonstrate that loss of mTOR causes BMF through down-regulation of Fancd2. Further, I was able to show that the mTOR kinase inhibitor pp242 enhanced the anti-tumor activity of conventional chemo-drugs in vitro and in vivo by suppressing FANCD2 and consequently augmenting DNA damage leading to apoptosis. Since the FA pathway is a DNA damage response pathway required for cellular resistance to anti-cancer drug-induced DNA damage, these studies unveil a novel strategy for the treatment of hematopoietic malignancies.
I am a Leukemia and Lymphoma Society Scholar (2008-2013). I’ve been a researcher for more than 27 years and started working at Cincinnati Children’s in 2003.
View a full list of my publications.