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.
Ifat Geron  1 ,  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
Affiliations
  • 1. Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
PMID: 18394555 DOI: 10.1016/j.ccr.2008.02.017
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.

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