Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by ineffectivehematopoiesis and a propensity for progression to bone marrow (BM) failure or acute leukemia. Despitetheir relatively high incidence, very little is known about their pathogenesis and their treatment remainsmainly palliative. This is largely due to the unavailability of good animal models and the challenges of the exvivo culture of primary MDS cells. Loss of the entire or part of chromosome 7 [del(7/7q)] is a recurrentcytogenetic abnormality in MDS, associated with unfavorable prognosis, strongly suggesting that one ormore critical genes - that so far remain elusive - reside in chromosome 7q. With recent breakthroughs inhuman pluripotent stem cell (hPSC) research - direct reprogramming and new genetic engineeringtechnologies - reverse genetics in an isogenic setting by precise disruption of genomic elements into theircognate genomic and cellular context - hitherto unthinkable for the human genome - are now a realisticprospect. Our goal is to harness cutting-edge reprogramming and genetic engineering technologies that weand others have developed to establish a novel hPSC-based model to study the cellular, molecular andgenetic pathogenesis of myelodysplasia. In preliminary studies, we have derived MDS-iPSC lines withchromosome 7q deletions from patient BM cells and found that they recapitulate potential disease-associated phenotypes: impaired cell proliferation and hematopoietic differentiation. In the proposed studywe plan to derive additional del(7q)- as well as isogenic karyotypically normal iPSCs, throughreprogramming and chromosome engineering, and characterize their phenotype in the undifferentiated stateand following hematopoietic differentiation. To identify genes with a role in MDS pathogenesis, we willperform 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 thestudy of myelodysplasia, generate insights into the cellular processes and molecular pathways affected andpotentially identify critical genes in the pathogenesis of MDS, bone marrow failure and preleukemia, ingeneral.!

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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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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