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Doulatov, Sergei, Ph.D.

Researcher Profiles

Researcher Profiles

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Sergei Doulatov, Ph.D.

Sergei Doulatov, Ph.D.

University of Washington

2018 Funding recipient

The impact of clonal heterogeneity on biology and treatment of SF3B1-mutant MDS

Discovery Research Grant 2018

PROJECT SUMMARY

MDS with ring sideroblasts (MDS-RS) is a common subtype of MDS (25% of patients) characterized by anemia and reduced ability to produce red blood cells. MDS-RS is considered relatively low-risk, however patients suffer morbidity and life-long transfusions. MDS-RS arises as a result of a genetic mutation in a gene SF3B1. My lab has established the first model of MDS-RS “in a dish” by using a method called ‘reprogramming’ in which we generate stem cells directly from MDS patients. During the first year of EvansMDS funding we have established stem cell lines from 4 MDS-RS patients and validated ring sideroblasts in 2 of them (Aim 1). We have shown the causative role for mutant SF3B1 protein in our model, and also shown that SF3B1 cooperates with other mutations (Aim 2). Many of these findings have been published in the recent manuscript from our lab. In collaboration with the Bradley lab at Fred Hutch we have carried out gene expression studies in our model and identified several genes targeted by SF3B1 that may be responsible for the red blood cell phenotype. We are currently using our model to test these target genes to develop a more mechanistic understanding of this disorder. Together with Dr. Bradley we have submitted an NIH R01 application to advance this project. The funding from EvansMDS foundation is instrumental in catalyzing this progress.

PUBLICATIONS

Jasper Hsu, Andreea Reilly, Brian J. Hayes, Courtnee A. Clough, Eric Q. Konnick, Beverly Torok-Storb, Suleyman Gulsuner, David Wu, Pamela S. Becker, Siobán B. Keel, Janis L. Abkowitz, Sergei Doulatov, Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic  syndromes. Blood 2019,  134:186-198, doi: 10.1182/blood.2018884338

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