Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors.

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Publication Year:
2008
Authors:
Ifat Geron, Annelie E Abrahamsson, Charlene F Barroga, Edward Kavalerchik, Jason Gotlib, John D Hood, Jeffrey Durocher, Chi Ching Mak, Glenn Noronha, Richard M Soll, Ayalew Tefferi, Ken Kaushansky, Catriona H M Jamieson
PubMed ID:
18394555
Funding Grants:
Scientific Abstract:
Polycythemia Vera (PV) is a myeloproliferative disorder (MPD) that is commonly characterized by mutant JAK2 (JAK2V617F) signaling, erythrocyte overproduction, and a propensity for thrombosis, progression to myelofibrosis, or acute leukemia. In this study, JAK2V617F expression by human hematopoietic progenitors promoted erythroid colony formation and erythroid engraftment in a bioluminescent xenogeneic immunocompromised mouse transplantation model. A selective JAK2 inhibitor, TG101348 (300 nM), significantly inhibited JAK2V617F+ progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG101348 treatment decreased GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibited STAT5 as well as GATA S310 phosphorylation. Thus, TG101348 may be an effective inhibitor of JAK2V617F+ MPDs in clinical trials.