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JAK2V617F-positive myeloproliferative neoplasm clones evoke paracrine DNA damage to adjacent normal cells through secretion of lipocalin-2.
MedLine Citation:
PMID:  25217696     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Genetic instability is strongly involved in cancer development and progression, and elucidating the mechanism could lead to novel therapeutics for preventing carcinogenesis. Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal myeloid disorders with high prevalence of JAK2V617F mutation, and its transformation to acute myeloid leukemia through accumulation of additional mutations is a major complication in MPN. Here, we showed that JAK2V617F-positive cells conferred paracrine DNA damage to neighboring normal cells as well as to themselves through increased reactive oxygen species (ROS). Through screening of candidate factors responsible for the effect, we found that lipocalin-2 (Lcn2) is overexpressed in JAK2V617F-positive cells and shRNA-mediated knockdown of Lcn2 significantly alleviated the paracrine DNA damage. Normal hematopoietic cells showed elevated ROS levels through increased intracellular iron levels when treated with lipocalin-2, which led to p53 pathway activation, increased apoptosis and decreased cellular proliferation. In contrast, JAK2V617F-positive cells did not suffer from lipocalin-2-induced growth suppression due to attenuated p53 pathway activation, which conferred a relative growth advantage to JAK2V617F-positive clones. In summary, we demonstrated that JAK2V617F-harboring cells cause paracrine DNA damage accumulation through secretion of lipocalin-2, which gives proliferative advantage to themselves and an increased risk for leukemic transformation to both JAK2V617F-positve and negative clones.
Authors:
Yuki Kagoya; Akihide Yoshimi; Takako Tsuruta-Kishino; Shunya Arai; Takashi Satoh; Shizuo Akira; Mineo Kurokawa
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-9-12
Journal Detail:
Title:  Blood     Volume:  -     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-9-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 American Society of Hematology.
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