TY - JOUR
T1 - The JAK kinase inhibitor CP-690,550 supresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation
AU - Manshouri, Taghi
AU - Quintás-cardama, Alfonso
AU - Nussenzveig, Roberto H.
AU - Gaikwad, Amos
AU - Estrov, Zeev
AU - Prchal, Josef
AU - Cortes, Jorge E.
AU - Kantarjian, Hagop M.
AU - Verstovsek, Srdan
PY - 2008/6
Y1 - 2008/6
N2 - The somatic activating janus kinase 2 mutation (JAK2)V617F is detectable in most patients with polycythemia vera (PV). Here we report that CP-690,550 exerts greater antiproliferative and pro-apoptotic activity against cells harboring JAK2V617F compared with JAK2WT. CP-690,550 treatment of murine factor-dependent cell Patersen-erythropoietin receptor (FDCP-EpoR) cells harboring human wild-type or V617F JAK2 resulted in inhibition of cell proliferation with a 50% inhibitory concentration (IC50) of 2.1 μM and 0.25 μM, respectively. Moreover, CP-690,550 induced a significant pro-apoptotic effect on murine FDCP-EpoR cells carrying JAK2V617F, whereas a lesser effect was observed for cells carrying wild-type JAK2. This activity was coupled with inhibition of phosphorylation of the key JAK2V617F-dependent downstream signaling effectors signal transducer and activator of transcription (STAT)3, STAT5, and v-akt murine thymoma viral oncogene homolog (AKT). Furthermore, CP-690,550 treatment of ex-vivo -expanded erythroid progenitors from JAK2V617F-positive PV patients resulted in specific, antiproliferative (IC50 = 0.2 μM) and pro-apoptotic activity. In contrast, expanded progenitors from healthy controls were less sensitive to CP-690,550 in proliferation (IC50 > 1.0 μM), and apoptosis assays. The antiproliferative effect on expanded patient progenitors was paralleled by a decrease in JAK2V617F mutant allele frequency, particularly in a patient homozygous for JAK2 V617F. Flow cytometric analysis of expanded PV progenitor cells treated with CP-690,550 suggests a possible transition towards a pattern of erythroid differentiation resembling expanded cells from normal healthy controls.
AB - The somatic activating janus kinase 2 mutation (JAK2)V617F is detectable in most patients with polycythemia vera (PV). Here we report that CP-690,550 exerts greater antiproliferative and pro-apoptotic activity against cells harboring JAK2V617F compared with JAK2WT. CP-690,550 treatment of murine factor-dependent cell Patersen-erythropoietin receptor (FDCP-EpoR) cells harboring human wild-type or V617F JAK2 resulted in inhibition of cell proliferation with a 50% inhibitory concentration (IC50) of 2.1 μM and 0.25 μM, respectively. Moreover, CP-690,550 induced a significant pro-apoptotic effect on murine FDCP-EpoR cells carrying JAK2V617F, whereas a lesser effect was observed for cells carrying wild-type JAK2. This activity was coupled with inhibition of phosphorylation of the key JAK2V617F-dependent downstream signaling effectors signal transducer and activator of transcription (STAT)3, STAT5, and v-akt murine thymoma viral oncogene homolog (AKT). Furthermore, CP-690,550 treatment of ex-vivo -expanded erythroid progenitors from JAK2V617F-positive PV patients resulted in specific, antiproliferative (IC50 = 0.2 μM) and pro-apoptotic activity. In contrast, expanded progenitors from healthy controls were less sensitive to CP-690,550 in proliferation (IC50 > 1.0 μM), and apoptosis assays. The antiproliferative effect on expanded patient progenitors was paralleled by a decrease in JAK2V617F mutant allele frequency, particularly in a patient homozygous for JAK2 V617F. Flow cytometric analysis of expanded PV progenitor cells treated with CP-690,550 suggests a possible transition towards a pattern of erythroid differentiation resembling expanded cells from normal healthy controls.
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U2 - 10.1111/j.1349-7006.2008.00817.x
DO - 10.1111/j.1349-7006.2008.00817.x
M3 - Article
C2 - 18482053
AN - SCOPUS:43849112498
SN - 1347-9032
VL - 99
SP - 1265
EP - 1273
JO - Cancer Science
JF - Cancer Science
IS - 6
ER -