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Abstract

Refractory anemia and erythroid dysplasia remain as one of the common clinical presentations and predominant causes of morbidity in patients with the blood malignancy, myelodysplastic syndromes (MDS). Better understanding of mechanisms underlying ineffective erythropoiesis in MDS is critically needed to develop novel therapeutic strategies. Reduced levels of the adaptor protein Dedicator of Cytokinesis 4 (DOCK4) is frequently observed in MDS patients due to epigenetic silencing and/or chromosomal deletions and is associated with dismal prognosis. In this dissertation, I investigated the functional and signaling role of DOCK4 during red blood cell development from a hematopoietic stem cell (HSC). Firstly, my studies have determined that reduced levels of DOCK4 results in erythroid dysplasia. Furthermore, re-expression of DOCK4 in MDS patient samples lacking DOCK4, partially reversed the observed erythroid defects suggesting that re-activation of the DOCK4 pathway might be therapeutically beneficial in MDS patients harboring DOCK4 defects. Secondly, as a means to reactivate the DOCK4 pathway in MDS, I identified targetable signaling networks downstream of DOCK4 by performing unbiased phosphoproteomics using HSCs expressing reduced levels of DOCK4. Finally, I demonstrate avenues for restoring the DOCK4 functions by targeting signaling elements downstream of DOCK4. Specifically, pharmacological inhibition of one of the identified candidates; PTPN6, is capable of relieving the differentiation block along the erythroid lineage in MDS patients expressing reduced levels of DOCK4. In summary, my work has uncovered novel functions and signaling networks regulated by DOCK4 that can be targeted to reverse the aberrant phenotypes arising due to reduced expression of DOCK4 in hematopoietic cells. Most importantly, my work has identified PTPN6 as a potential therapeutic target to alleviate anemia in MDS.

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