that consists of four members ( JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]). These members share structural and functional homologies defined by seven JAK homology ( JH) domains (Panel A). These seven domains may be categorized into the JH1 kinase MK-0431 domain, the JH2 pseudokinase domain, the SRC homology 2 (SH2)–like domain (that mediates binding to phosphorylated tyrosine residues), and the FERM (protein 4.1, ezrin, radixin, and moesin) domain (required for JAK interaction with cytokine receptors). The myeloproliferative neoplasm−associated V617F mutation in JAK2 is located in the JH2 autoregulatory domain (red line). After engagement of the receptor by a cognate cytokine, JAKs undergo transphosphorylation and in turn phosphorylate critical residues in the receptor and downstream signaling molecules (Panel B).
The latter include the STAT (signal transducers and activators of transcription) family of latent, cytosolic DNA-binding proteins. Phosphorylated STATs (blue rectangles with red dots) dimerize and travel into the nucleus, where they regulate the expression of genes Semagacestat involved in control of cell proliferation and survival, angiogenesis, immunity, and encoding of a large array of secreted proinflammatory cytokines. Different cytokine receptors preferentially use one or more JAKs. Thus, a great pleomorphism of effects is produced by inhibition of JAK1 and JAK2. On the contrary, JAK3 is activated only by prepayment cytokine receptors containing the γc subunit (in green on the right). G-CSF denotes granulocyte colony-stimulating factor, GM-CSF granulocyte–macrophage colony-stimulating factor, LIF leukemia inhibitory factor, and OSM oncostatin M.to other yet-to-be-discovered mutated genes in patients with myeloproliferative neoplasms with wild-type JAK2.6 INCB018424 is the best characterized of an expanding family of inhibitors with a certain degree of specificity for JAK2 versus other Janus kinases, although most are roughly equimolar inhibitors of JAK1 and JAK2.
None of the available molecules discriminate between mutated and wild-type JAK2. Paradoxically, in the study reported on by Verstovsek et al such a lack of specificity turned supplier Pimecrolimus out to be an advantage, since INCB018424 was similarly effective in patients without the JAK2 V617F mutation. 2 Some of the activity of the JAK1 and JAK2 inhibitors may be due to upstream alterations other than mutations that activate JAK2 in these diseases.6 The study also raised issues that are pertinent to the pathogenesis of myelofibrosis. The first issue concerns the role of inflammation. Clinical improvement was correlated with a reduction in plasma levels of many inflammatory cytokines; this effect was mainly attributable to JAK1 inhibition (Fig. 1). It will be important to understand whether an inflammatory microenvironment has a role in disease initiation and progression, in particular in the development of bone marrow fibrosis.
If so, earlier initiation of therapy with a JAK1 and JAK2 inhibitor could further improve the outcome. Second, the prompt shrinking of an enlarged spleen cannot be attributed only to the inhibition of neoplastic cell proliferation in the spleen; elucidation of the underlying price HA-1077 mechanisms could prove relevant for the identification of new targets for therapy. Finally, the results reported challenge the theory that the development of a specific JAK2 inhibitor is essential; as a matter of fact, concomitant inhibition of JAK1 proved as clinically relevant as inhibition of JAK2.7 .