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

被引：113

作者：

Geron, Ifat ^{[1
]}

Abrahamsson, Annelie E. ^{[1
]}

Barroga, Charlene F. ^{[1
]}

Kavalerchik, Edward ^{[1
]}

Gotlib, Jason ^{[2
]}

Hood, John D. ^{[3
]}

Durocher, Jeffrey ^{[4
]}

Mak, Chi Ching ^{[3
]}

Noronha, Glenn ^{[3
]}

Soll, Richard M. ^{[3
]}

Tefferi, Ayalew ^{[5
]}

Kaushansky, Ken ^{[1
]}

Jamieson, Catriona H. M. ^{[1
]}

机构：

[1] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[2] Stanford Univ, Dept Med, Stanford, CA 94305 USA

[3] TargeGen Inc, San Diego, CA 92121 USA

[4] Transgenomic Inc, Gaithersburg, MD 20878 USA

[5] Mayo Clin, Dept Med, Rochester, MN 55905 USA

来源：

CANCER CELL | 2008年 / 13卷 / 04期

关键词：

D O I：

10.1016/j.ccr.2008.02.017

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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, TG1 01348 (300 nM), significantly inhibited JAK2V617F(+) progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG1 01348 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, TG1 01348 may be an effective inhibitor of JAK2V617F(+) MPDs in clinical

引用

页码：321 / 330

页数：10

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