Imatinib effect on growth and signal transduction in polycythemia vera

Amos Gaikwad, Srdan Verstovsek, Donghoon Yoon, Ko Tung Chang, Taghi Manshouri, Roberto Nussenzveig, Jorge Cortes, William Vainchenker, Josef T. Prchal

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)931-938
Number of pages8
JournalExperimental Hematology
Volume35
Issue number6
DOIs
StatePublished - Jun 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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