Author/Authors :
Geron، نويسنده , , Ifat and Abrahamsson، نويسنده , , Annelie E. and Barroga، نويسنده , , Charlene F. and Kavalerchik، نويسنده , , Edward and Gotlib، نويسنده , , Jason and Hood، نويسنده , , John D. and Durocher، نويسنده , , Jeffrey and Mak، نويسنده , , Chi Ching and Noronha، نويسنده , , Glenn and Soll، نويسنده , , Richard M. and Tefferi، نويسنده , , Ayalew and Kaushansky، نويسنده , , Ken and Jamieson، نويسنده , , Catriona H.M.، نويسنده ,
Abstract :
Summary
themia 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.
