Figure 1.

Overview of signaling pathways in myeloproliferative neoplasms. The Janus Kinase 2 (JAK2) protein is intracellularly connected with receptors such as the granulocyte-colony stimulating factor receptor (G-CSFR), the thrombopoietin receptor (myeloproliferative leukemia virus oncogene [MPL]), and erythropoietin receptor (EPOR). Activation of these receptors by their appropriate ligands (G-CSF, thrombopoietin [TPO] and EPO, respectively) induces phosphorylation of JAK2. Phosphorylated JAK2 serves as a docking station for signal transducer and activator of transcription 5 (STAT5) which initiates further downstream signaling pathways. Activated JAK2 may also stimulate the activation of other pathways such as mitogen activated protein-kinase (MAPK), phosphoinositide 3-kinase (PI3K) or the nuclear factor kappa B pathway (NF-κB) through activation of AKT (protein kinase B). NF-κB activation can also be mediated through activation of toll-like receptors (TLR) (not shown). Mutations in JAK2, calreticulin (CALR) or MPL genes result in uncontrolled activation of these proliferative pathways, enhanced cellular survival and production of various inflammatory cytokines, together promoting development of hematologic malignancies. Lightning symbol indicates occurrence of mutations in myeloproliferative neoplasm-associated driver genes (MPL, CALR and JAK2) coding for the corresponding proteins.