The acute lymphoblastic leukemia-associated JAK2 L611S mutant induces tumorigenesis in nude mice

Megumi Tago, Kenji Tago, Kazuya Sumi, Miyuki Abe, Eriko Yokota, Tomoyuki Oshio, Yoshiko Sonoda, Tadashi Kasahara

Research output: Contribution to journalArticle

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Abstract

JAK2 plays important roles in the regulation of a variety of cellular processes including cell migration, proliferation, and protection from apoptosis. Recently the L611S point mutation in JAK2 has been identified in a child with acute lymphoblastic leukemia. Here we analyzed the mechanism by which JAK2 exhibits its oncogenicity. In BaF3 murine hematopoietic cells, L611S mutant increased the expression of antiapoptotic proteins including X chromosome-linked inhibitor of apoptosis protein, inhibitor of apoptosis protein, and Bcl-XL. We also showed that JAK2 L611S mutant protects BaF3 cells from cytokine withdrawal-induced apoptotic cell death and leads to cytokine-independent cell growth. Furthermore BaF3 cells expressing JAK2 L611S mutant gained the ability to induce tumorigenesis in nude mice. The L611S mutant also exhibited malignancy, including prompt invasion and spreading into various organs, leading to rapid lethality of the mice. Finally we showed that a specific JAK2 inhibitor, AG490, potently inhibited cytokine-independent cell growth induced by JAK2 L611S mutant via the induction of apoptotic cell death. In addition, treatment with AG490 significantly inhibited the JAK2 L611S mutant-induced tumorigenesis in nude mice. Thus, our results both in vitro and in vivo strongly suggest that L611S mutant of JAK2 harbors potent oncogenic activity, and this probably requires the antiapoptotic signaling pathway.

Original languageEnglish
Pages (from-to)12680-12690
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number19
DOIs
Publication statusPublished - 2009 May 8

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Nude Mice
Inhibitor of Apoptosis Proteins
Carcinogenesis
Cell growth
Cell death
Cytokines
Chromosomes
Ports and harbors
Cell Death
X-Linked Inhibitor of Apoptosis Protein
Cells
Cytoprotection
Apoptosis
X Chromosome
Growth
Point Mutation
Cell Movement
Cell Proliferation
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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The acute lymphoblastic leukemia-associated JAK2 L611S mutant induces tumorigenesis in nude mice. / Tago, Megumi; Tago, Kenji; Sumi, Kazuya; Abe, Miyuki; Yokota, Eriko; Oshio, Tomoyuki; Sonoda, Yoshiko; Kasahara, Tadashi.

In: Journal of Biological Chemistry, Vol. 284, No. 19, 08.05.2009, p. 12680-12690.

Research output: Contribution to journalArticle

Tago, Megumi ; Tago, Kenji ; Sumi, Kazuya ; Abe, Miyuki ; Yokota, Eriko ; Oshio, Tomoyuki ; Sonoda, Yoshiko ; Kasahara, Tadashi. / The acute lymphoblastic leukemia-associated JAK2 L611S mutant induces tumorigenesis in nude mice. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 19. pp. 12680-12690.
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