This proposal will investigate the mechanisms by which Fanconi anemia (FA) proteins regulate cellular response to oxidative stress in the context of hematopoiesis. The process of FA disease progression is characterized by bone marrow failure (BMF), clonal proliferation of hematopoietic stem and progenitor (HSC/P) cells, and progression to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While clinical observations have established a correlation between abnormal accumulation of ROS and FA BMF/leukemic evolution, the molecular pathways in which FA proteins function to modulate physiologic oxidative stress have not been defined. We recently found that FA BM cells accumulated high levels of ROS generated by inflammation and that FA HSC/P cells were extremely sensitive to ROS-induced hematopoietic suppression. We have also shown that abnormal accumulation of ROS played a critical role in the evolution of leukemic clones in FA mouse model. Our most recent identification of the FANCD2- FOXO3a complex and preliminary characterization of impaired anti-oxidant defense in primary BM cells from FA patients open new research opportunities to extend this project to the renewal period.
In Aim 1, we will test the hypothesis that physiologic oxidative stress contributes to BMF and progression to clonal hematopoiesis in FA through influencing HSC/P cell proliferation and apoptosis, by assessing the effect of inflammatory ROS on proliferation and apoptosis of HSC/P cells from FA children at three different stages (BMF, MDS, and AML) of disease progression and in a "humanized" NOG/SGM3 mouse xenograft model.
In Aim 2, we will 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 focus on major oxidative stress response pathways involving FOXO3a and cellular anti-oxidant defense systems.
In Aim 3, we will test the hypothesis that increased inflammatory ROS and vulnerability of chromosomal DNA to oxidative damage would provide a potential genetic mechanism for FA genomic instability, 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 using two FA preleukemic models. The knowledge gained from these studies may lead to a new avenue of research designed to further explore the pathogenic role of oxidative stress not only in FA but also in cancer- related hematological diseases in general. In addition, new insights on the potential integration of the FA proteins in other oxidative-stress signaling pathways can suggest new targets for therapeutic prevention and treatment of BMF and cancer progression of these diseases.

Public Health Relevance

Oxidative stress has been implicated in the pathogenesis of many human diseases including Fanconi anemia (FA), a blood disease associated with bone marrow failure and cancer. The goal of this project is to define the function of FA proteins in the maintenance of blood cell survival under physiologic oxidative stress. The proposed study will provide valuable information for therapeutic prevention and treatment of bone marrow failure and cancer progression of not only FA but also other blood diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076712-08
Application #
8452195
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Qasba, Pankaj
Project Start
2004-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$359,250
Indirect Cost
$123,630
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Du, Wei; Amarachintha, Surya; Erden, Ozlem et al. (2016) The Fanconi anemia pathway controls oncogenic response in hematopoietic stem and progenitor cells by regulating PRMT5-mediated p53 arginine methylation. Oncotarget :
Du, W; Amarachintha, S; Wilson, A et al. (2016) The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion. Leukemia :
Du, Wei; Amarachintha, Surya; Wilson, Andrew F et al. (2016) Hyper-active non-homologous end joining selects for synthetic lethality resistant and pathological Fanconi anemia hematopoietic stem and progenitor cells. Sci Rep 6:22167
Du, Wei; Amarachintha, Surya; Wilson, Andrew F et al. (2016) SCO2 Mediates Oxidative Stress-Induced Glycolysis to Oxidative Phosphorylation Switch in Hematopoietic Stem Cells. Stem Cells 34:960-71
Sertorio, Mathieu; Amarachintha, Surya; Wilson, Andrew et al. (2016) Loss of Fancc Impairs Antibody-Secreting Cell Differentiation in Mice through Deregulating the Wnt Signaling Pathway. J Immunol 196:2986-94
Li, Xiaoli; Zhang, Tingting; Wilson, Andrew et al. (2015) Transcriptional profiling of Foxo3a and Fancd2 regulated genes in mouse hematopoietic stem cells. Genom Data 4:148-149
Li, Xiaoli; Li, Jie; Wilson, Andrew et al. (2015) Fancd2 is required for nuclear retention of Foxo3a in hematopoietic stem cell maintenance. J Biol Chem 290:2715-27
Du, Wei; Amarachintha, Surya; Erden, Ozlem et al. (2015) Fancb deficiency impairs hematopoietic stem cell function. Sci Rep 5:18127
Zhang, Tingting; Wilson, Andrew F; Mahmood Ali, Abdullah et al. (2015) Loss of Faap20 Causes Hematopoietic Stem and Progenitor Cell Depletion in Mice Under Genotoxic Stress. Stem Cells 33:2320-30
Amarachintha, Surya; Sertorio, Mathieu; Wilson, Andrew et al. (2015) Fanconi Anemia Mesenchymal Stromal Cells-Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll-Like Receptor Signaling. Stem Cells 33:3382-96

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