Abstract
The discovery of the activating V617F mutation in Janus kinase 2 (JAK2) has been decisive for the understanding of myeloproliferative neoplasms (MPN). Activated JAK2 signaling by JAK2, CALR, and MPL mutations has become a focus for the development of targeted therapies for patients with MPN. JAK2 inhibitors now represent a standard of clinical care for certain forms of MPN and offer important benefits for MPN patients. However, several key aspects remain unsolved regarding the targeted therapy of MPN with JAK2 inhibitors, such as reducing the MPN clone and how to avoid or overcome a loss of response. Here, we summarize the current knowledge on the structure and signaling of JAK2 as central elements of MPN pathogenesis and feature benefits and limitations of therapeutic JAK2 targeting in MPN.
Highlights
Janus kinases (JAKs) constitute a family of intracellular, non-receptor tyrosine kinases.They are associated with their corresponding cell surface receptors and transduce signals from cytokines, as well as some hormones, such as growth hormone and prolactin [1].Mediation of extracellular signals via JAKs activates intracellular messenger pathways, impacting hematopoiesis, metabolism, and immune responses [2,3,4]
Janus kinase 2 (JAK2) and the additional Janus kinase family members JAK1, JAK3, and TYK2 share a similar structure with seven Janus homology (JH)-domains (JH1–JH7, Figure 1) [5,6]
It has become clear that the pseudokinase domain has a regulatory impact on the JAK2 kinase domain via phosphorylation of S523 and Y570, mediating basal autoinhibition, which is reversed by stimulation of the associated cytokine receptor [9,10,11]
Summary
Janus kinases (JAKs) constitute a family of intracellular, non-receptor tyrosine kinases. They are associated with their corresponding cell surface receptors and transduce signals from cytokines, as well as some hormones, such as growth hormone and prolactin [1]. Mediation of extracellular signals via JAKs activates intracellular messenger pathways, impacting hematopoiesis, metabolism, and immune responses [2,3,4]. The discovery that most BCR-ABL1-negative myeloproliferative neoplasms (MPN) carry an activating JAK2 mutation has moved this tyrosine kinase into the center of interest and has led to refined diagnostic criteria for these disease entities, development of new prognostic models, and the introduction of JAK inhibitors into clinical practice. We review the role of JAK2 in myeloproliferative neoplasms (Supplementary Materials).
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