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.
N1 - Funding Information:
We are indebted to Dennis Young for his expert assistance with FACS-Aria analysis and sorting. We are also grateful to Dr. Inder Verma for providing lentiviral backbone vectors and Dr. Gary Gilliland and Dr. Ross Levine for providing JAK2 plasmids used in the construction of JAK2 lentiviral vectors. We are also thankful to our patients with PV for contributing samples to this study and to the faculty of the Stanford Division of Hematology and the Mayo Clinic for identifying patients for participation, in particular Lenn Fechter, Dr. Stanley Schrier, Dr. Lawrence Leung, and Dr. Caroline Berube. This work was supported in part by grants from the California Institute for Regenerative Medicine and the Mizrahi Family Foundation to E.K., C.B., and C.H.M.J., the National Institutes of Health (K23HL04409) to J.G., and an unrestricted gift from TargeGen Inc.
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
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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 -