The JAK kinase inhibitor CP-690,550 supresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation

Taghi Manshouri, Alfonso Quintás-cardama, Roberto H. Nussenzveig, Amos Gaikwad, Zeev Estrov, Josef Prchal, Jorge E. Cortes, Hagop M. Kantarjian, Srdan Verstovsek

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1265-1273
Number of pages9
JournalCancer Science
Volume99
Issue number6
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

Fingerprint

Janus Kinases
Polycythemia Vera
Janus Kinase 2
Mutation
Inhibitory Concentration 50
Growth
Erythropoietin Receptors
STAT3 Transcription Factor
Thymoma
tofacitinib
Oncogenes
Gene Frequency
Stem Cells
Phosphorylation
Cell Proliferation
Apoptosis
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Manshouri, T., Quintás-cardama, A., Nussenzveig, R. H., Gaikwad, A., Estrov, Z., Prchal, J., ... Verstovsek, S. (2008). The JAK kinase inhibitor CP-690,550 supresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. Cancer Science, 99(6), 1265-1273. https://doi.org/10.1111/j.1349-7006.2008.00817.x

The JAK kinase inhibitor CP-690,550 supresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. / Manshouri, Taghi; Quintás-cardama, Alfonso; Nussenzveig, Roberto H.; Gaikwad, Amos; Estrov, Zeev; Prchal, Josef; Cortes, Jorge E.; Kantarjian, Hagop M.; Verstovsek, Srdan.

In: Cancer Science, Vol. 99, No. 6, 01.06.2008, p. 1265-1273.

Research output: Contribution to journalArticle

Manshouri, T, Quintás-cardama, A, Nussenzveig, RH, Gaikwad, A, Estrov, Z, Prchal, J, Cortes, JE, Kantarjian, HM & Verstovsek, S 2008, 'The JAK kinase inhibitor CP-690,550 supresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation', Cancer Science, vol. 99, no. 6, pp. 1265-1273. https://doi.org/10.1111/j.1349-7006.2008.00817.x
Manshouri, Taghi ; Quintás-cardama, Alfonso ; Nussenzveig, Roberto H. ; Gaikwad, Amos ; Estrov, Zeev ; Prchal, Josef ; Cortes, Jorge E. ; Kantarjian, Hagop M. ; Verstovsek, Srdan. / The JAK kinase inhibitor CP-690,550 supresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. In: Cancer Science. 2008 ; Vol. 99, No. 6. pp. 1265-1273.
@article{80660e066bba4fde99e854fca9c13db7,
title = "The JAK kinase inhibitor CP-690,550 supresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation",
abstract = "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.",
author = "Taghi Manshouri and Alfonso Quint{\'a}s-cardama and Nussenzveig, {Roberto H.} and Amos Gaikwad and Zeev Estrov and Josef Prchal and Cortes, {Jorge E.} and Kantarjian, {Hagop M.} and Srdan Verstovsek",
year = "2008",
month = "6",
day = "1",
doi = "10.1111/j.1349-7006.2008.00817.x",
language = "English (US)",
volume = "99",
pages = "1265--1273",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "6",

}

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 - 2008/6/1

Y1 - 2008/6/1

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.

UR - http://www.scopus.com/inward/record.url?scp=43849112498&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43849112498&partnerID=8YFLogxK

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

VL - 99

SP - 1265

EP - 1273

JO - Cancer Science

JF - Cancer Science

SN - 1347-9032

IS - 6

ER -