Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors

Cancer Cell. 2008 Apr;13(4):321-30. doi: 10.1016/j.ccr.2008.02.017.


Polycythemia Vera (PV) is a myeloproliferative disorder (MPD) that is commonly characterized by mutant JAK2 (JAK2V617F) signaling, erythrocyte overproduction, and a propensity for thrombosis, progression to myelofibrosis, or acute leukemia. In this study, JAK2V617F expression by human hematopoietic progenitors promoted erythroid colony formation and erythroid engraftment in a bioluminescent xenogeneic immunocompromised mouse transplantation model. A selective JAK2 inhibitor, TG101348 (300 nM), significantly inhibited JAK2V617F+ progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG101348 treatment decreased GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibited STAT5 as well as GATA S310 phosphorylation. Thus, TG101348 may be an effective inhibitor of JAK2V617F+ MPDs in clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Cell Differentiation / drug effects*
  • Erythroid Precursor Cells / drug effects
  • Erythroid Precursor Cells / enzymology*
  • Erythroid Precursor Cells / pathology*
  • Female
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Male
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Phenylalanine / genetics
  • Polycythemia Vera / enzymology*
  • Polycythemia Vera / pathology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects
  • Stem Cell Transplantation
  • Valine / genetics


  • Protein Kinase Inhibitors
  • Phenylalanine
  • Janus Kinase 2
  • Valine