JAK2 inhibitors: what's the true therapeutic potential? - PubMed (original) (raw)

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JAK2 inhibitors: what's the true therapeutic potential?

Fabio P S Santos et al. Blood Rev. 2011 Mar.

Abstract

Physicians treating patients with the classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) (polycythemia vera [PV], essential thrombocythemia [ET] and primary myelofibrosis [PMF]) traditionally had few therapeutic drugs available. Spurred by the discovery of activating mutation of the JAK2 tyrosine kinase (JAK2 V617F mutation) in patients with Ph-negative MPNs several years ago, several JAK2 inhibitors were synthesized and are currently undergoing clinical trials in patients with PMF, PV and ET. Initial results from these studies have shown that these drugs can markedly reduce spleen size and alleviate constitutional symptoms, increase weight and improve exercise capacity in MF patients, thus improve quality of their life, which is significant clinical benefit. In ET and PV JAK2 inhibitor therapy may efficiently control blood cell count, as well as improve splenomegaly and control disease related symptoms. JAK2 inhibitors are a novel class of agents with promising results for treating patients with MF, PV and ET. In this article we will review the current evidence regarding the role of JAK2 mutations in the pathogenesis of Ph-negative MPNs and summarize results from the most recent clinical trials with JAK2 inhibitors in these disorders. JAK2 inhibitors are a novel class of agents with promising results for treating patients with MF, PV and ET.

Copyright © 2010 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Conflicts of interest: None

Figures

Figure 1

Figure 1. JAK2 structure and mutation sites

The V617F mutation locates in the pseudokinase domain (JH2 domain) which regulates activity of the TK domain (JH1 domain). Exon 12 mutations of JAK2 (described in patients with JAK2 V617F negative polycythemia vera) cluster in residues F537-E543 and locate between the pseudokinase and SH2-like domain

Figure 2

Figure 2. Signalling pathways activated by JAK2

Binding of the putative ligand to cytokine receptors leads to receptor dimerization and approximation of two JAK2 molecules, which trans-phosphorylate and activate each other. Activated JAK2 molecules initiate several distinct signalling pathways. Phosphorylation of STATs (STAT5 depicted in the figure) leads to STAT dimerization, nuclear translocation, binding to DNA and activation of expression of target genes. Other pathways that may be activated by JAKs include the Ras/Raf/MAPKinases and the PI3K/Akt/mTOR pathway.

Figure 3

Figure 3

Biochemical structures of selected JAK2 inhibitors in clinical trials.

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