Fanconi anemia (FA) is a major inherited bone marrow (BM) failure syndrome with extremely high risk of developing acute myeloid leukemia (AML). The only curable treatment for this devastating disease is stem cell and gene therapies through BM transplantation. We recently described cell-autonomous defects of FA hematopoietic stem cells (HSCs) 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. More recently, our preliminary studies show that genetic deletion of Cdc42 in mice causes massive mobilization of HSCs from BM niche. Furthermore, we have developed CASIN, a Cdc42 activity-specific inhibitor, which can specifically, transiently, and reversibly down regulate Cdc42 and Cdc42-regulated signaling activities, allowing successful engraftment of CD34+ human blood progenitors as well as transplanted congenic murine HSCs without myeloablative or irradiation preconditioning. Using a FA knockout (Fanca) mouse model we have shown that preconditioning of Fanca-/- mice with CASIN allows significant engraftment of WT or FANCA gene-corrected Fanca-/- HSCs in the absence of myeloablative or irradiation conditioning. These preliminary data suggest that Cdc42 controls HSC residence in the BM niche through regulating cell adhesion. 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 wild-type or gene-corrected HSC to engraft. The goals of the project are to study the mechanism of Cdc42 targeting in the context of HSC mobilization and BM niche engraftment, and ultimately to develop a novel preclinical regimen by targeting Cdc42 to 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 project presents the first mechanistic study aimed at targeting a critical HSC-niche interaction regulator in a significant health-care setting. The knowledge gained from the proposed study will not only improve mechanistic understanding of stem cell mobilization and engraftment in the context of stem cell transplantation, but also lead to a new avenue of research designed to target Cdc42 for developing innovative therapeutic regimens for stem cell and gene therapies in leukemia and BM failure diseases.

Public Health Relevance

Bone marrow transplantation (BMT) is the only curable treatment for certain devastating blood diseases such as leukemia and bone marrow (BM) failure syndromes. However, three major hurdles that have been hampering scientific and clinical advance in the BMT field: 1) ineffective mobilization of patient stem cells;2) hypersensitivity of recipient patients to pre-conditioning regimens;and 3) inefficient delivery of genetically corrected patient stem cells to the BM niche. The goal of the project is to develop a novel preclinical regimen to improve BMT therapy for leukemia and BM failure diseases, clinical settings in which intensive preconditioning and scarce stem cell numbers critically limit success.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157537-03
Application #
8403833
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2011-02-01
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$298,427
Indirect Cost
$103,377
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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
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, 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
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
Du, Wei; Erden, Ozlem; Wilson, Andrew et al. (2014) Deletion of Fanca or Fancd2 dysregulates Treg in mice. Blood 123:1938-47

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