Selective Inhibition of JAK2-Driven Erythroid Differentiation of Polycythemia Vera Progenitors

Ifat Geron, Annelie E. Abrahamsson, Charlene F. Barroga, Edward Kavalerchik, Jason Gotlib, John D. Hood, Jeffrey Durocher, Chi Ching Mak, Glenn Noronha, Richard M. Soll, Ayalew Tefferi, Ken Kaushansky, Catriona H.M. Jamieson

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)321-330
Number of pages10
JournalCancer cell
Volume13
Issue number4
DOIs
StatePublished - Apr 8 2008

Keywords

  • CELLCYCLE
  • CHEMBIO
  • STEMCELL

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Geron, I., Abrahamsson, A. E., Barroga, C. F., Kavalerchik, E., Gotlib, J., Hood, J. D., Durocher, J., Mak, C. C., Noronha, G., Soll, R. M., Tefferi, A., Kaushansky, K., & Jamieson, C. H. M. (2008). Selective Inhibition of JAK2-Driven Erythroid Differentiation of Polycythemia Vera Progenitors. Cancer cell, 13(4), 321-330. https://doi.org/10.1016/j.ccr.2008.02.017