@article{Myelodysplastic:1977,
      recid = {1977},
      author = {Sundaravel, Sriram},
      title = {Mechanism of Action of a Signaling Protein DOCK4 in  Myelodysplastic Syndromes},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2019-08},
      pages = {146},
      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.},
      url = {http://knowledge.uchicago.edu/record/1977},
      doi = {https://doi.org/10.6082/uchicago.1977},
}