TY - JOUR
T1 - Imatinib effect on growth and signal transduction in polycythemia vera
AU - Gaikwad, Amos
AU - Verstovsek, Srdan
AU - Yoon, Donghoon
AU - Chang, Ko Tung
AU - Manshouri, Taghi
AU - Nussenzveig, Roberto
AU - Cortes, Jorge
AU - Vainchenker, William
AU - Prchal, Josef T.
N1 - Funding Information:
This work is supported by grants T32 DK60445-01 (A.G. and R.N., J.T.P.), R01HL50077-12 (J.T.P.), 1P01CA108671-01A2 (NCI) Myeloproliferative Disorders (MPD) Consortium; Project #1 (P1 Prchal): Genetic Basis of Polycythemia Vera (J.T.P., A.G.) and MSM 0021620806 (K.C. and J.T.P.) from the Ministry of Education of the Czech Republic and Ligue Nationale contre le Cancer (W.V.).
PY - 2007/6
Y1 - 2007/6
N2 - Objective: An activating mutation of Janus kinase 2 (JAK2) in majority of polycythemia vera (PV) and other myeloproliferative disorders was reported. As imatinib inhibits several tyrosine kinases, we studied its effect in PV. Patients and Methods: We employed FDCP reporter cells expressing wild-type JAK2 and mutant JAK2V617F to study the efficacy of imatinib by cell proliferation assay and its effect on several cell-signaling events. Imatinib's efficacy was also examined on in vitro expanded native human erythroid progenitors. In addition, analysis of the percent JAK2 T-allele and phospho-signal transducer and activator of transcription-5 (STAT5) in granulocytes of PV patients following imatinib therapy was assessed. Results: Imatinib showed a specific time- and dose-dependent growth inhibitory effect on FDCP cells expressing JAK2V617F, wherein we observed imatinib's inactivation of JAK2, STAT5 and cKIT proteins. In vitro expanded human PV erythroid progenitors were more sensitive to imatinib than normal erythroid progenitors and FDCP cells expressing JAK2V617F, with growth inhibition at concentrations attainable in vivo. In an ongoing clinical study, a PV patient showed strong correlation between the percent JAK2 T-allele and his responsiveness to imatinib therapy. Conclusion: Our data elucidate the therapeutic benefit of imatinib seen in some PV patients. Our data suggest that JAK2/STAT5 and cKIT activation may be integrated. To our knowledge, this is the first report demonstrating imatinib's effect on PV erythroid progenitors. These studies underscore the limitation of experiments using cell lines expressing the gene of interest.
AB - Objective: An activating mutation of Janus kinase 2 (JAK2) in majority of polycythemia vera (PV) and other myeloproliferative disorders was reported. As imatinib inhibits several tyrosine kinases, we studied its effect in PV. Patients and Methods: We employed FDCP reporter cells expressing wild-type JAK2 and mutant JAK2V617F to study the efficacy of imatinib by cell proliferation assay and its effect on several cell-signaling events. Imatinib's efficacy was also examined on in vitro expanded native human erythroid progenitors. In addition, analysis of the percent JAK2 T-allele and phospho-signal transducer and activator of transcription-5 (STAT5) in granulocytes of PV patients following imatinib therapy was assessed. Results: Imatinib showed a specific time- and dose-dependent growth inhibitory effect on FDCP cells expressing JAK2V617F, wherein we observed imatinib's inactivation of JAK2, STAT5 and cKIT proteins. In vitro expanded human PV erythroid progenitors were more sensitive to imatinib than normal erythroid progenitors and FDCP cells expressing JAK2V617F, with growth inhibition at concentrations attainable in vivo. In an ongoing clinical study, a PV patient showed strong correlation between the percent JAK2 T-allele and his responsiveness to imatinib therapy. Conclusion: Our data elucidate the therapeutic benefit of imatinib seen in some PV patients. Our data suggest that JAK2/STAT5 and cKIT activation may be integrated. To our knowledge, this is the first report demonstrating imatinib's effect on PV erythroid progenitors. These studies underscore the limitation of experiments using cell lines expressing the gene of interest.
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U2 - 10.1016/j.exphem.2007.03.012
DO - 10.1016/j.exphem.2007.03.012
M3 - Article
C2 - 17533047
AN - SCOPUS:34249019530
SN - 0301-472X
VL - 35
SP - 931
EP - 938
JO - Experimental Hematology
JF - Experimental Hematology
IS - 6
ER -