title: Alox5 Blockade Eradicates JAK2V617F-Induced Polycythemia Vera in Mice.
abstract: Myeloproliferative neoplasms such as polycythemia vera (PV), which are associated with the JAK mutation V617F, remain incurable despite progress in the use of JAK2 inhibitors for treatment of some of these diseases. In this study, we employed mice that undergo JAK2V617F-induced PV as a tool to explore new candidate targets for therapy. Our investigations focused on the lipid metabolic enzyme arachidonate 5-lipoxygenase (Alox5), which we found to be strongly upregulated by JAK2V617F in hematopoietic cells in vitro and in vivo Notably, genetic deletion of Alox5 or its inhibition in mice with a bioactive small-molecule inhibitor was sufficient to attenuate PV development. This therapeutic effect was associated with induction of a blockade in cell-cycle progression and also with apoptosis in PV cells. Genetic loss exerted an inhibitory effect on PV-initiating cells. Similarly, Alox5 inhibition was sufficient to suppress colony formation in human JAK2V617F-expressing CD34+cells. Mechanistic investigations showed that Alox5 inhibition reduced AKT activation and decreased β-catenin expression in JAK2V617F-expressing cells. Together, our results define Alox5 as a key genetic effector of JAK2V617F in driving PV, and they identify this enzyme as a candidate therapeutic target to treat this refractory myeloproliferative neoplasm. Cancer Res; 77(1); 164-74. ©2016 AACR.
authors: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Yaoyu
authors: Y
authors: Chen
authors: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Yi
authors: Y
authors: Shan
authors: Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York.
authors: Min
authors: M
authors: Lu
authors: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Ngoc
authors: N
authors: DeSouza
authors: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Zhiru
authors: Z
authors: Guo
authors: Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York.
authors: Ronald
authors: R
authors: Hoffman
authors: Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai, PR China. shaoguang.li@umassmed.edu lab7182@tongji.edu.cn.
authors: Aibin
authors: A
authors: Liang
authors: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. shaoguang.li@umassmed.edu lab7182@tongji.edu.cn.
authors: Shaoguang
authors: S
authors: Li
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000235:genetics*; D020024:Leukotriene Antagonists / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011087:Polycythemia Vera / Q000235:genetics*; D016133:Polymerase Chain Reaction
chemical_list: D020024:Leukotriene Antagonists; D001094:Arachidonate 5-Lipoxygenase; D053614:Janus Kinase 2; C063449:zileuton; D006918:Hydroxyurea