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JAK 2‐ V 617 F ‐mediated signalling is dependent on lipid rafts and statins inhibit JAK 2‐ V 617 F ‐dependent cell growth
Author(s) -
Griner Lori N.,
McGraw Kathy L.,
Johnson Joseph O.,
List Alan F.,
Reuther Gary W.
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12103
Subject(s) - lipid raft , janus kinase 2 , chemistry , cancer research , erythropoietin , statin , microbiology and biotechnology , cholesterol , receptor , biology , biochemistry , endocrinology
Summary Aberrant JAK 2 signalling plays an important role in the aetiology of myeloproliferative neoplasms ( MPN s). JAK 2 inhibitors, however, do not readily eliminate neoplastic MPN cells and thus do not induce patient remission. Further understanding JAK 2 signalling in MPN s may uncover novel avenues for therapeutic intervention. Recent work has suggested a potential role for cellular cholesterol in the activation of JAK 2 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 JAK 2‐ V 617 F kinase localizes to lipid rafts and that JAK 2‐ V 617 F ‐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 ‐ C o A ) reductase inhibitors, widely used to treat hypercholesterolaemia, induce apoptosis and inhibit JAK 2‐V617F‐dependent cell growth. These cells are more sensitive to statin treatment than non‐ JAK 2‐ V 617 F ‐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 JAK 2‐ V 617 F signalling is dependent on lipid rafts and that statins may be effective in a potential therapeutic approach for MPN s.