JAK2‐V617F‐mediated signalling is dependent on lipid rafts and statins inhibit JAK2‐V617F‐dependent cell growth

• Published in: British journal of haematology Vol. 160; no. 2; pp. 177 - 187
• Main Authors: Griner, Lori N., McGraw, Kathy L., Johnson, Joseph O., List, Alan F., Reuther, Gary W.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01.01.2013
• Subjects: Apoptosis - drug effects; beta-Cyclodextrins - pharmacology; Biological and medical sciences; Cell Line, Tumor - drug effects; Cell Line, Tumor - enzymology; Cells, Cultured - drug effects; Cells, Cultured - enzymology; cholesterol; Cholesterol - analysis; Cholesterol - physiology; Colony-Forming Units Assay; Drug Evaluation, Preclinical; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - enzymology; Hematologic and hematopoietic diseases; Humans; JAK2‐V617F; Janus Kinase 2 - genetics; Janus Kinase 2 - physiology; K562 Cells - drug effects; K562 Cells - enzymology; Leukemia, Erythroblastic, Acute - enzymology; Leukemia, Erythroblastic, Acute - pathology; Leukemia, Megakaryoblastic, Acute - enzymology; Leukemia, Megakaryoblastic, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; lipid raft; Medical sciences; Megakaryocyte Progenitor Cells - drug effects; Megakaryocyte Progenitor Cells - enzymology; Membrane Lipids - physiology; Membrane Microdomains - drug effects; Membrane Microdomains - physiology; Mutation, Missense; Myeloproliferative Disorders - blood; Myeloproliferative Disorders - enzymology; myeloproliferative neoplasms; Phosphorylation - drug effects; Point Mutation; Protein Processing, Post-Translational - drug effects; Signal Transduction - drug effects; Simvastatin - pharmacology; STAT5 Transcription Factor - metabolism; statin; Tumors; Cell proliferation; myeloproliferative neoplasms; Lipid raft; Hematology; Enzyme; JAK2 protein tyrosine kinase; Transferases; Enzyme inhibitor; Lipids; Hemopathy; Statin derivative; Cholesterol; Myeloproliferative syndrome; Signal transduction; Cancerology; statin; JAK2-V617F; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Protein-tyrosine kinase; Antilipemic agent
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.12103

Summary Aberrant JAK2 signalling plays an important role in the aetiology of myeloproliferative neoplasms (MPNs). JAK2 inhibitors, however, do not readily eliminate neoplastic MPN cells and thus do not induce patient remission. Further understanding JAK2 signalling in MPNs may uncover novel avenues for therapeutic intervention. Recent work has suggested a potential role for cellular cholesterol in the activation of JAK2 by the erythropoietin receptor and in the development of an MPN‐like disorder in mice. Our study demonstrates for the first time that the MPN‐associated JAK2‐V617F kinase localizes to lipid rafts and that JAK2‐V617F‐dependent signalling is inhibited by lipid raft disrupting agents, which target membrane cholesterol, a critical component of rafts. We also show for the first time that statins, 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase inhibitors, widely used to treat hypercholesterolaemia, induce apoptosis and inhibit JAK2‐V617F‐dependent cell growth. These cells are more sensitive to statin treatment than non‐JAK2‐V617F‐dependent cells. Importantly, statin treatment inhibited erythropoietin‐independent erythroid colony formation of primary cells from MPN patients, but had no effect on erythroid colony formation from healthy individuals. Our study is the first to demonstrate that JAK2‐V617F signalling is dependent on lipid rafts and that statins may be effective in a potential therapeutic approach for MPNs.