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

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53 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Manshouri, T., Quintás-cardama, A., Nussenzveig, R. H., Gaikwad, A., Estrov, Z., Prchal, J., Cortes, J. E., Kantarjian, H. M., & 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