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

Cancer Sci. 2008 Jun;99(6):1265-73. doi: 10.1111/j.1349-7006.2008.00817.x.


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 JAK2(V617F) compared with JAK2(WT). 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 (IC(50)) of 2.1 microM and 0.25 microM, respectively. Moreover, CP-690,550 induced a significant pro-apoptotic effect on murine FDCP-EpoR cells carrying JAK2(V617F), whereas a lesser effect was observed for cells carrying wild-type JAK2. This activity was coupled with inhibition of phosphorylation of the key JAK2(V617F)-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 JAK2(V617F)-positive PV patients resulted in specific, antiproliferative (IC(50) = 0.2 microM) and pro-apoptotic activity. In contrast, expanded progenitors from healthy controls were less sensitive to CP-690,550 in proliferation (IC(50) > 1.0 microM), and apoptosis assays. The antiproliferative effect on expanded patient progenitors was paralleled by a decrease in JAK2(V617F) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Cell Cycle
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Erythroid Precursor Cells / drug effects
  • Erythroid Precursor Cells / metabolism
  • Erythropoietin / metabolism
  • Flow Cytometry
  • Humans
  • Immunoprecipitation
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mutation / genetics*
  • Phosphorylation / drug effects
  • Piperidines
  • Polycythemia Vera / drug therapy*
  • Polycythemia Vera / enzymology
  • Polycythemia Vera / pathology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Transport
  • Pyrimidines / therapeutic use*
  • Pyrroles / therapeutic use*
  • Receptors, Erythropoietin / genetics
  • Receptors, Erythropoietin / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects


  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Receptors, Erythropoietin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Erythropoietin
  • tofacitinib
  • Janus Kinase 2