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JAK2-V617F-mediated signalling is dependent on lipid rafts and statins inhibit
JAK2-V617F-dependent cell growth
#MMPMID23157224
Griner LN
; McGraw KL
; Johnson JO
; List AF
; Reuther GW
Br J Haematol
2013[Jan]; 160
(2
): 177-87
PMID23157224
show ga
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.
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