Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by ineffective hematopoiesis and a propensity for progression to bone marrow (BM) failure or acute leukemia. Despite their relatively high incidence, very little is known about their pathogenesis and their treatment remains mainly palliative. This is largely due to the unavailability of good animal models and the challenges of the ex vivo culture of primary MDS cells. Loss of the entire or part of chromosome 7 [del(7/7q)] is a recurrent cytogenetic abnormality in MDS, associated with unfavorable prognosis, strongly suggesting that one or more critical genes - that so far remain elusive - reside in chromosome 7q. With recent breakthroughs in human pluripotent stem cell (hPSC) research - direct reprogramming and new genetic engineering technologies - reverse genetics in an isogenic setting by precise disruption of genomic elements into their cognate genomic and cellular context - hitherto unthinkable for the human genome - are now a realistic prospect. Our goal is to harness cutting-edge reprogramming and genetic engineering technologies that we and others have developed to establish a novel hPSC-based model to study the cellular, molecular and genetic pathogenesis of myelodysplasia. In preliminary studies, we have derived MDS-iPSC lines with chromosome 7q deletions from patient BM cells and found that they recapitulate potential disease- associated phenotypes: impaired cell proliferation and hematopoietic differentiation. In the proposed study we plan to derive additional del(7q)- as well as isogenic karyotypically normal iPSCs, through reprogramming and chromosome engineering, and characterize their phenotype in the undifferentiated state and following hematopoietic differentiation. To identify genes with a role in MDS pathogenesis, we will perform a screen of candidate genes residing in chromosome 7q for rescue of proliferation in our del(7q)- hPSCs. These studies, using powerful new technologies, will provide a novel valuable resource for the study of myelodysplasia, generate insights into the cellular processes and molecular pathways affected and potentially identify critical genes in the pathogenesis of MDS, bone marrow failure and preleukemia, in general. !

Public Health Relevance

Progress in understanding the etiology and in effectively treating Myelodysplastic Syndromes (MDS) is currently hampered by the scarcity of tools to study this disease. We propose to establish a new MDS model, harnessing cutting-edge human pluripotent stem cell and genetic engineering technologies, and use it as a novel and powerful platform to investigate the cell biology, molecular pathogenesis and genetic basis of this disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Di Fronzo, Nancy L
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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