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Dasatinib inhibits progenitor cell proliferation from polycythaemia vera

M Wappl1, E Jaeger, B Streubel

  • 1Medical University of Vienna, Austria.

European Journal of Clinical Investigation
|August 23, 2008
PubMed
Abstract

Insights

Dasatinib significantly inhibits polycythaemia vera (PV) progenitor cell growth in vitro. This effect occurs at pharmacological concentrations, though JAK2 V617F mutation levels remain unchanged.

Area of Science:

  • Hematology
  • Molecular Biology
  • Pharmacology

Background:

  • Polycythaemia vera (PV) is often associated with the Janus kinase 2 (JAK2) V617F mutation.
  • The JAK2(V617F) mutation is not the sole molecular driver in PV.
  • Dasatinib is under investigation for PV treatment, necessitating study of its cellular effects.

Purpose of the Study:

  • To investigate the in vitro effects of dasatinib on clonal progenitor cell growth in patients with PV.
  • To determine the impact of dasatinib on both endogenous erythroid colony (EEC) formation and cytokine-stimulated colony growth.

Main Methods:

  • Peripheral blood mononuclear cells from PV patients, chronic myeloid leukaemia (CML) patients, and controls were treated with dasatinib (0.1–500 nm).
  • Colony growth was assessed with and without exogenous cytokines (IL-3, GM-CSF, EPO).
  • Real-time PCR quantified JAK2(V617F) transcript levels.

Main Results:

  • Dasatinib (10 nm) suppressed EEC growth in PV by 89% in a dose-dependent manner at pharmacological concentrations.
  • Both erythroid and myeloid colony growth were significantly inhibited by dasatinib.
  • While PV progenitor cells were potently inhibited, JAK2(V617F) transcript levels did not decrease.

Conclusions:

  • Dasatinib markedly inhibits the proliferative capacity of PV progenitor cells.
  • The mechanism of PV progenitor suppression by dasatinib may involve an unidentified molecular target, as JAK2(V617F) transcript levels were unaffected.

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