title: JAK2V617F+ myeloproliferative neoplasm clones evoke paracrine DNA damage to adjacent normal cells through secretion of lipocalin-2.
abstract: 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 (MPNs) are clonal myeloid disorders with a high prevalence of JAK2V617F mutation, and transformation to acute myeloid leukemia through accumulation of additional mutations is a major complication in MPNs. Here, we showed that JAK2V617F(+) cells conferred paracrine DNA damage to neighboring normal cells as well as to themselves through increased reactive oxygen species (ROS). We screened candidate factors responsible for the effect and found that lipocalin-2 (Lcn2) is overexpressed in JAK2V617F(+) cells and that short hairpin RNA-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(+) cells did not suffer from lipocalin-2-induced growth suppression resulting from attenuated p53 pathway activation, which conferred a relative growth advantage to JAK2V617F(+) 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(+) and JAK2V617F(-) clones.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kagoya
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
authors.forename: Akihide
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
authors.forename: Takako
authors.initials: T
authors.lastname: Tsuruta-Kishino
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
authors.forename: Shunya
authors.initials: S
authors.lastname: Arai
authors.affiliation: Laboratory of Host Defense, World Premier International Research Center Initiative, Immunology Frontier Research Center, and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Laboratory of Host Defense, World Premier International Research Center Initiative, Immunology Frontier Research Center, and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D005260:Female; D006410:Hematopoiesis / Q000502:physiology; D019190:Iron Overload / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism*; D009570:Nitriles; D015513:Oncogene Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D019899:Paracrine Communication / Q000187:drug effects / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D009570:Nitriles; D015513:Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C071332:Lcn2 protein, mouse; C540383:ruxolitinib; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2