Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies

Abstract

Hematopoiesis is the cumulative result of intricately regulated signaling pathways that are mediated by cytokines and their receptors. Studies conducted over the past 10 to 15 years have revealed that hematopoietic cytokine receptor signaling is largely mediated by a family of tyrosine kinases termed Janus kinases (JAKs) and their downstream transcription factors, termed STATs (signal transducers and activators of transcription). Aberrations in these pathways, such as those caused by the recently identified JAK2(V617F) mutation and translocations of the JAK2 gene, are underlying causes of leukemias and other myeloproliferative disorders. This review discusses the role of JAK/STAT signaling in normal hematopoiesis as well as genetic abnormalities associated with myeloproliferative and myelodisplastic syndromes. This review also summarizes the status of several small molecule JAK2 inhibitors that are currently at various stages of clinical development. Several of these compounds appear to improve the quality of life of patients with myeloproliferative disorders by palliation of disease-related symptoms. However, to date, these agents do not seem to significantly affect bone marrow fibrosis, alter marrow histopathology, reverse cytopenias, reduce red cell transfusion requirements, or significantly reduce allele burden. These results suggest the possibility that additional mutational events might be associated with the development of these neoplasms, and indicate the need for combination therapies as the nature and significance of these additional molecular events is better understood.

Keywords: JAK; JAK2 inhibitors; STAT; cytokine receptor; myeloproliferative disorders.

Figure 1.

Schematic representation of cytokine receptor families. The structure of 5 superfamilies and their respective members are depicted. Note: not drawn to scale. Adapted from Baker et al.

Figure 2.

Structure of Janus kinases (JAKs). JAKs harbor 4 functional domains: the FERM domain, the SH2 domain, the pseudotyrosine kinase domain, and a catalytically active tyrosine kinase domain. Although the JH2 region is not a functional tyrosine kinase, this domain negatively regulates the activity of JAK proteins. Also shown are the FERM and SH2 domains, which serve as receptor association and phosphotyrosine binding domains, respectively, and the JAK2^V617F mutation that is found in MPDs. Depicted here are the domain boundaries for JAK2. Adapted from Baker et al.

Figure 3.

Signaling pathways mediated by JAKs. Ligand binding to cytokine receptors induces their dimerization. JAKs, which bind to the receptor via their SH2 domains, undergo transphosphorylation and subsequently phosphorylate STATs. The activated STATs dimerize and translocate to the nucleus, whereby they activate or repress target gene promoters. STATs can also be directly activated by Src kinases. In this model, JAKs phosphorylate the receptor and create binding sites for STATs. In addition to JAKs and STATs, cytokine receptors also activate additional signaling pathways involving proteins such as Akt and ERK. Adapted from Baker et al.

Figure 4.

Structure of STAT proteins. STATs harbor 6 domains: the N-terminal, coiled-coil, DNA binding, linker, SH2, and transactivation domains. The N-terminal and DNA binding domains cooperate in binding to the promoters of target genes. Regulatory phosphotyrosine (pY) and phosphoserine residues (pS) are also shown. Adapted from Baker et al.

Figure 5.

JAK2 translocations discovered in myeloid and lymphoid leukemias. All translocations fuse the multimerization subunit(s) of partner proteins to the JAK2 catalytic kinase (JH1) domain. The amino acid boundaries of each protein in the chimeras are indicated numerically where available, and their associated disease conditions are highlighted. HLH = helix-loop-helix domain; CCD = coiled-coil domain(s); DD = dimerization domain; RHD = Runt homology domain; OLI = oligomerization domain; PCR = proteasome/cyclosome repeated motifs; S2 = SSBP2 fused at LiSH; LiSH = Lis homology motif; PD = paired domain.

Figure 6.

JAK2 mutations found in the clinic. Point mutations, duplications, and insertions identified in MPNs map to exons 12 to 15, revealing the N-terminal half of the regulatory pseudokinase (JH2) domain as a hotspot for kinase activation.

Figure 7.

JAK2 inhibitors in clinical trials.