JAK2 Inhibitors for Myelofibrosis: Why are They Effective in Patients with and Without JAK2V617F Mutation?

Fabio      P. S. Santos; Srdan      Verstovsek

doi:10.2174/187152012803529727

Abstract

An activating mutation (V617F) in the pseudokinase domain of the Janus kinase (JAK)-2 tyrosine kinase has been described in 90% of patients with polycythemia vera (PV) and 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (MF). The discovery of JAK2V617F stirred the development of JAK2 inhibitors for treatment of patients with MF, ET and PV. Similar to other tyrosine kinase (TK) inhibitors in current use, JAK2 inhibitors target the adenosine triphosphate (ATP) binding site at the TK domain and not the pseudokinase domain, thus affecting both mutated and wild-type kinases. In fact, clinical trials of these compounds have demonstrated improvements in constitutional symptoms and splenomegaly in patients with both mutated and wild-type JAK2 MF. It is believed that these drugs may act not only through inhibition of neoplastic cell proliferation, but also by downregulating signaling through proinflammatory cytokine receptors. In this article, we review the current state of JAK2 inhibitors and discuss why these drugs could be a valuable addition to the treatment armamentarium for patients with and without the JAK2V617F mutation.

Keywords: Essential thrombocythemia, JAK2 inhibitor, JAK2V617F, Myelofibrosis, Polycythemia vera, CYTOKINE RECEPTORS, JAK TYROSINE KINASES, proinflammatory state, erythropoietin, microenvironmental cells