Targeting JAK2 in the therapy of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are a group of stem cell diseases, including polycythemia vera, essential thrombocythemia and primary myelofibrosis. Currently, there is no curative therapy for these diseases other than bone marrow transplant; therefore there is an apparent need for palliative treatment. MPNs are frequently associated with activating mutations in JAK2; small-molecule drugs targeting this molecule have entered clinical trials.

In this review novel JAK2 inhibitors are discussed and alternative approaches to inhibiting their transforming potential are highlighted. Current clinical approaches do not only aim at blocking JAK2 activity, but also at reducing its stability and expression are highlighted, including inhibition of heat shock protein 90 (HSP90) and deacetylases (DAC) have the potential to significantly enhance the efficacy of JAK2 inhibitors.

Preliminary results from clinical trials indicate the feasibility and efficacy of JAK2-targeted approaches. However, JAK2 inhibitor treatment is limited by dose-dependent toxicity and combination treatment might be required. The discovery of JAK2 mutations that cause secondary resistance in vitro would further highlight the need for the development of next-generation JAK2 inhibitors and novel synergistic approaches.