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Unraveling the Role of DDX41 in Hematopoiesis and MDS


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Myelodysplastic syndromes (MDS) are bone marrow failure disorders arising from defects in blood-forming stem cells resulting in stem cell expansion and decreased production of mature blood cells. MDS in adults is largely thought to be acquired, but the recent identification of a familial form of adult-onset MDS linked to germline mutations in the DEAD-box Helicase 41 gene (DDX41) challenges this dogma. Although this form of MDS is rare, lessons learned from familial forms of human diseases often provide information that is more broadly applicable to acquired forms of a disease that arise from sporadic and/or complex genetic changes. Germline mutations in DDX41 disrupt its function such that insufficiency of normal levels of DDX41 is thought to contribute to MDS formation. DDX41 plays several roles in cellular homeostasis, thus it is unclear which aspects are aberrant when DDX41 is mutated and how dysfunction of these processes contribute to MDS. To address this question, we have established a zebrafish model of ddx41 deficiency, which is one of the first animal models for studying the in vivo requirements of Ddx41 in hematopoiesis. Human and zebrafish DDX41 are highly conserved, thus we anticipate that our studies in zebrafish will be informative for understanding the function of human DDX41 in hematopoiesis. Zebrafish is an easily manipulated vertebrate model system that has been used extensively to study the basis of both benign and malignant hematopoiesis including MDS. We aim to utilize the advantages of the zebrafish to uncover how Ddx41 regulates hematopoiesis and identify novel therapeutic targets for the treatment of MDS.



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