Pharmacologic Restoration of PP2A Activity by FTY720 as a Novel Therapy for Polycythemia Vera
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Series/Report no.:2011 Edward F. Hayes Graduate Research Forum. 25th
Polycythemia Vera (PV) is an incurable rare myeloproliferative disorder driven by Jak2 V617F with few viable treatment options and no curative therapy available. With the intention of developing a curative treatment modality, we examined the interplay between the known tumor suppressor PP2A and the driver of PV, Jak2 V617F. We found PP2A to be inactivated by Jak2 V617F activity and that forced PP2A activity is produces a loss of Jak2 V617F activity and function. Of particular interest we found that the clinically relevant PP2A activator/immunosuppressant FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride, fingolimod, Gilenya) to activate PP2A in PV model cell lines and primary patient samples. Treatment with FTY720 produced a reduction in Jak2 protein coupled with reduced cellular proliferation in cells expressing Jak2 V617F. The anti-leukemic effects of FTY720 were found to be independent of immunosuppressive activity. To conclude, we found that PP2A activation in cells expressing Jak2 V617F by FTY720 reduced Jak2 levels and proliferation and did so in a mechanism independent of immunosuppression.
Professional Biological Sciences: 3rd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
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