演題詳細

一般口演 / Oral Session

【E】一般口演 33 (Oral Session 33) :MDS/MPN:Basic Research 1

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日程
2013年10月11日(金)
時間
14:25 - 15:25
会場
第14会場 / Room No.14 (札幌市教育文化会館 3F 研修室305)
座長・司会
桐戸 敬太 (Keita Kirito):1
1:Department of Hematology, University of Yamanashi, Japan
 
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JAK2V617F mutation evokes paracrine DNA damage to adjacent cells and drives leukemic transformation

演題番号 : OS-1-166

籠谷 勇紀 (Yuki Kagoya):1、吉見 昭秀 (Akihide Yoshimi):1、鶴田 貴子 (Takako Tsuruta):1、片岡 圭亮 (Keisuke Kataoka):1、荒井 俊也 (Shunya Arai):1、黒川 峰夫 (Mineo Kurokawa):1

1:Department of Hematology and Oncology, The University of Tokyo, Japan

 

Myeloproliferative neoplasms (MPN) are clonal myeloid disorders associated with a high prevalence of JAK2V617F mutation, and one of the most dismal complications is their transformation to acute myeloid leukemia (AML). Curiously, the transformed AML cells frequently lack the JAK2 mutation. Here, we investigated the pathogenesis underlying these phenomena using MPN mouse model induced by transplantation of JAK2V617F-IRES-GFP-transduced bone marrow cells. Surprisingly, we observed increased γ-H2AX foci formation in both GFP-positive and GFP-negative hematopoietic stem/progenitor cells, indicating that JAK2V617F-positive clones confer genetic instability to both themselves and neighboring normal cells in a paracrine manner. Consistently, when normal hematopoietic cells were cultured in media conditioned by JAK2V617F-positive cells, γ-H2AX foci formation was significantly increased, which resulted in the activation of p53 pathway and increased apoptosis rate of the cultured cells. To clarify the mechanism of JAK2V617F-induced paracrine DNA damage, we conducted a thorough screen for shRNA and found that knocking down the adipokine lipocalin-2 (LCN2) strikingly alleviated the JAK2V617F-mediated DNA damage response. Conversely, LCN2 exposure to hematopoietic cells resulted in the elevated intracellular ROS levels and increased DNA damage. In summary, these results elucidate that JAK2V617F-positive cells evoke DNA damage to adjacent normal clones via the secretion of LCN2, which provides promising therapeutic targets for preventing the leukemic transformation from MPN.

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