TY - JOUR
T1 - Selective Inhibition of JAK2-Driven Erythroid Differentiation of Polycythemia Vera Progenitors
AU - Geron, Ifat
AU - Abrahamsson, Annelie E.
AU - Barroga, Charlene F.
AU - Kavalerchik, Edward
AU - Gotlib, Jason
AU - Hood, John D.
AU - Durocher, Jeffrey
AU - Mak, Chi Ching
AU - Noronha, Glenn
AU - Soll, Richard M.
AU - Tefferi, Ayalew
AU - Kaushansky, Ken
AU - Jamieson, Catriona H.M.
PY - 2008/4/8
Y1 - 2008/4/8
N2 - 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.
AB - 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.
KW - CELLCYCLE
KW - CHEMBIO
KW - STEMCELL
UR - http://www.scopus.com/inward/record.url?scp=41249098776&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41249098776&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2008.02.017
DO - 10.1016/j.ccr.2008.02.017
M3 - Article
C2 - 18394555
AN - SCOPUS:41249098776
VL - 13
SP - 321
EP - 330
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 4
ER -