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

doi:10.1016/j.ccr.2008.02.017

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

Hematology

Research output: Contribution to journal › Article › peer-review

110 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 language	English (US)
Pages (from-to)	321-330
Number of pages	10
Journal	Cancer cell
Volume	13
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2008.02.017
State	Published - Apr 8 2008

Keywords

CELLCYCLE
CHEMBIO
STEMCELL

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Selective Inhibition of JAK2-Driven Erythroid Differentiation of Polycythemia Vera Progenitors. / Geron, Ifat; Abrahamsson, Annelie E.; Barroga, Charlene F.; Kavalerchik, Edward; Gotlib, Jason; Hood, John D.; Durocher, Jeffrey; Mak, Chi Ching; Noronha, Glenn; Soll, Richard M.; Tefferi, Ayalew; Kaushansky, Ken; Jamieson, Catriona H.M.

In: Cancer cell, Vol. 13, No. 4, 08.04.2008, p. 321-330.

Research output: Contribution to journal › Article › peer-review

Geron, Ifat ; Abrahamsson, Annelie E. ; Barroga, Charlene F. ; Kavalerchik, Edward ; Gotlib, Jason ; Hood, John D. ; Durocher, Jeffrey ; Mak, Chi Ching ; Noronha, Glenn ; Soll, Richard M. ; Tefferi, Ayalew ; Kaushansky, Ken ; Jamieson, Catriona H.M. / Selective Inhibition of JAK2-Driven Erythroid Differentiation of Polycythemia Vera Progenitors. In: Cancer cell. 2008 ; Vol. 13, No. 4. pp. 321-330.

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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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