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Sergei Doulatov, Ph.D.
The impact of clonal heterogeneity on biology and treatment of SF3B1-mutant MDS

Sergei Doulatov, Ph.D.

University of Washington

2018 Funding recipient

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

EvansMDS Discovery Research Grant 2018

PROJECT SUMMARY

In MDS with ring sideroblasts red blood cells do not develop properly causing severe anemia. We know that these red blood cells harbor defective mitochondria. We also know that mutations in splicing factor SF3B1 often occur in patients with this disorder. It is currently not understood how mutations in SF3B1 cause defective mitochondria, and how this leads to anemia. This is preventing researchers from finding more effective ways of treating this disorder.

We will use an approach called cell reprogramming, in which we take a cell from patient bone marrow and turn it into a stem cell. This ‘pluripotent’ stem cell retains the genome of the starting cell and its oncogenic mutations. We will use patient stem cells to create ring sideroblasts in a dish. In collaboration with Dr. Robert Bradley, an expert in splicing at the Fred Hutchinson Cancer Center, we will uncover the connection between SF3B1, mitochondria, and red blood cells.

MDS patients with ring sideroblasts generally have a good prognosis. However, it is not known how other mutations influence outcome and treatment response. Because reprogramming captures the entire genome, we can unravel how interactions between SF3B1 and cooperating mutations alters the disease. We are especially interested in how these mutations modify responses to a promising new class of drugs called spliceosomal inhibitors. This information would directly translate into improved treatment strategies for MDS patients.