The polycythemia vera-associated Jak2 V617F mutant induces tumorigenesis in nude mice.
The somatic Jak2 mutation (V617F) was identified in most patients with polycythemia vera (PV). Here, we show that the activating Jak2 V617F mutant completely protected Ba/F3 cells from cytokine withdrawal-induced apoptotic cell death. Interestingly, Ba/F3 cells expressing Jak2 V617F mutant induced rapid tumorigenesis in nude mice, leading to rapid death. Whereas an injection of Ba/F3 cells expressing wild-type Jak2 had no effect, an injection of Ba/F3 cells expressing Jak2 V617F mutant promptly invaded and spread into various distinct organs, such as the liver and spleen. Strikingly, Jak2 inhibitor, AG490 potently inhibited cytokine-independent cell growth induced by the Jak2 V617F mutant. Also, treatment with AG490 effectively delayed Jak2 V617F mutant-induced tumorigenesis in nude mice. Thus, our results both in vitro and in vivo suggest that Jak2 harboring V617F mutation is a potent oncogene able to promote cell transformation and tumorigenesis.
Abe
Miyuki
M
Department of Biochemistry, Faculty of Pharmacology, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Funakoshi-Tago
Megumi
M
Tago
Kenji
K
Kamishimoto
Jun
J
Aizu-Yokota
Eriko
E
Sonoda
Yoshiko
Y
Kasahara
Tadashi
T