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JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation
Author(s) -
Oku Seido,
Takenaka Katsuto,
Kuriyama Takuro,
Shide Kotaro,
Kumano Takashi,
Kikushige Yoshikane,
Urata Shingo,
Yamauchi Takuji,
Iwamoto Chika,
Shimoda Haruko K.,
Miyamoto Toshihiro,
Nagafuji Koji,
Kishimoto Junji,
Shimoda Kazuya,
Akashi Koichi
Publication year - 2010
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2010.08249.x
Subject(s) - mapk/erk pathway , pi3k/akt/mtor pathway , stat5 , cancer research , cell growth , protein kinase b , ruxolitinib , ly294002 , phosphorylation , janus kinase 2 , signal transduction , biology , microbiology and biotechnology , immunology , myelofibrosis , genetics , bone marrow
Summary The acquired JAK2 V617F mutation is observed in the majority of patients with BCR‐ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR‐ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild‐type Jak2 . We found that Jak2 V617F mutation, but not wild‐type Jak2 enhanced LAP expression in NB4‐derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation.