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JAK2 V617F mutation in MPN pathogenesis: Insights and potential therapeutic implications
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The JAK2V617F mutation is a common driver mutation in MPN and leads to persistent activation of the JAK/STAT signaling pathway, which is pivotal in promoting cell proliferation, differentiation, and anti-apoptosis.1 Whilst JAK inhibitors are widely used in clinical practice for the treatment of MPN, they are not curative and therefore require long‐term treatment; which is associated with serious physical, psychological and economical burdens for patients.1 Easing the long‐term treatment burden and potentially curing MPN will require a detailed understanding of its pathogenesis in order to elucidate new therapeutic targets and combination therapy strategies.1 Zhang et al.1explored the roles of the JAK2V617F mutation in MPN, including mechanisms of non‐JAK/STAT pathways, cellular methylation regulation, accumulation of DNA damage, and cardiovascular effects, with a view to informing combination therapy options for MPN. We summarize key findings from their review recently published in Cancer.1 |
| Key learnings |
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In addition to JAK/STAT activation, the JAK2V617F mutation affects non-JAK/STAT pathways, such as PI3K/AKT/mTOR and MAPK, enhancing MPN progression through increased cell survival, DNA damage accumulation, and cardiovascular effects. |
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JAK2V617F influences epigenetic mechanisms, particularly DNA and histone methylation, by altering the activity of key enzymes like TET2 and DNMT3A, thus contributing to MPN pathogenesis. |
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Cardiovascular complications are common in MPN, with JAK2V617F promoting thrombosis via endothelial dysfunction, increased oxidative stress, and heightened RBC adhesion to the vasculature. |
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JAK inhibitor therapy is an effective treatment but not curative. Combined therapeutic approaches targeting multiple pathways (e.g., JAK/STAT and PI3K/AKT) could offer improved outcomes. |
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This research emphasizes the need for multidrug therapy in MPN to improve outcomes beyond JAK inhibition alone. |
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Addressing cardiovascular risks and exploring epigenetic modulation could lead to better patient management strategies. |
Abbreviations: JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MPN, myeloproliferative neoplasms; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; RBC, red blood cell; STAT, signal transducer and activator of transcription.
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