The Fanconi pathway repairs collapsed and stalled DNA-replication forks through homologous recombination repair (HRR) and translesional synthesis (TLS);thereby maintaining genomic integrity during S phase of the cell cycle. Congenital absence of any Fanconi protein results in Fanconi Anemia (FA);a disorder that is characterized during early stages by bone marrow failure (BMF). BMF is hypothesized to occur as unrepaired DNA damage triggers apoptosis in FA hematopoietic stem cells (HSC) and progenitor cells. Patients who survive the BMF stage of FA have a tendency to develop bone marrow dysplasia with clonal progression. This is hypothesized to be caused by accumulating mutations that induce resistance to cell cycle checkpoints and/or the apoptotic response to DNA-damage. FA patients exhibit steady state granulocytopenia and susceptibility to infection. Our studies suggest that impaired """"""""emergency granulopoiesis"""""""" (EG) during infectious challenge also contributes to immuno-deficiency in FA. Under normal circumstances, EG-related cytokines stimulate immediate granulocyte release from the bone marrow, followed by expansion of HSC and granulocyte/monocyte progenitors (GMP). This proliferative phase involves S phase-shortening. We found that expression of Fanconi C and F increased in primary murine GMP treated with IL1? and other cytokines that mediate the EG response. And, we determined that FancC deficient mice are unable to mount an in vivo EG-response. Instead, we found that repeated episodes of EG-stimulation result in pancytopenia, BMF, and death in the majority of FancC-/- mice. We also found that the adverse effects of EG stimulation in FancC-/- mice are blocked by an IL1-R antagonist. We hypothesize that repeated, failed episodes of emergency granulopoiesis accelerate bone marrow failure in FA. And, that unsuccessful EG episodes provide opportunity for mutations that result in clonal progression. This hypothesis will be pursued through three aims:
AIM 1 : Define mechanisms of Fanconi pathway activation and DNA-repair during EG. Wt, FancC- deficient, or FancA-deficient murine bone marrow cells will be treated with EG-related cytokines and analyzed for Fanconi pathway activation and DNA-repair. In vivo studies will be performed with various EG stimuli.
AIM 2 : Identify molecular mechanisms involved in EG-related bone marrow failure in FA. We will also use the models described above to determine if EG-related cytokines induce apoptosis in Fanc-deficient bone marrow in association with cell cycle checkpoint activation.
AIM 3 : Determine if multiple failed episodes of EG facilitate clonal progression in FA: We will use these models to determine if blocking specific cytokines prevents clonal progression during repeated EG episodes. The goal of these studies is to define the role of ineffective EG episodes in BMF and clonal progression in FA. These studies may suggest therapeutic approaches that could be rapidly translated to the clinic.
Fanconi Anemia (FA) is an inherited disorder characterized by the inability to repair DNA-damage, and characterized by bone marrow failure early in childhood. In these studies, we investigate the role of recurrent inflammatory challenge on bone marrow failure and clonal progression in FA. We hypothesize that the stress of bone marrow stem cell proliferation and commitment to differentiation contribute to these processes.
|Hu, Liping; Huang, Weiqi; Hjort, Elizabeth E et al. (2016) The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis. J Biol Chem 291:4107-20|
|Hjort, Elizabeth E; Huang, Weiqi; Hu, Liping et al. (2016) Bcr-abl regulates Stat5 through Shp2, the interferon consensus sequence binding protein (Icsbp/Irf8), growth arrest specific 2 (Gas2) and calpain. Oncotarget :|
|Huang, W; Luan, C-H; Hjort, E E et al. (2016) The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia. Leukemia 30:1502-9|
|Wang, Hao; Bei, Ling; Shah, Chirag A et al. (2015) HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1. J Immunol 194:5375-87|
|Sakamoto, Kathleen M; Grant, Steven; Saleiro, Diana et al. (2015) Targeting novel signaling pathways for resistant acute myeloid leukemia. Mol Genet Metab 114:397-402|
|Hu, Liping; Huang, Weiqi; Hjort, Elizabeth et al. (2013) Increased Fanconi C expression contributes to the emergency granulopoiesis response. J Clin Invest 123:3952-66|
|Shah, Chirag A; Bei, Ling; Wang, Hao et al. (2013) The leukemia-associated Mll-Ell oncoprotein induces fibroblast growth factor 2 (Fgf2)-dependent cytokine hypersensitivity in myeloid progenitor cells. J Biol Chem 288:32490-505|