Signaling pathways involved in the pathogenesis of MPNs. (A) JAK2V617F is attached to the cytosolic juxtamembrane region of dimeric cytokine receptors, such as EpoR or MPL (TpoR) but can also be attached to the cytosolic region of other JAK2-using cytokine receptors, such as the IFN-γ receptor 2 chain. When bound to homodimeric cytokine receptors, JAK2V617F induces constitutive signaling via STAT5, STAT3, RAS-MAPK, and PI-3′K-Akt pathways, which all regulate gene expression and promote survival, proliferation, and differentiation of committed myeloid progenitors. Constitutive STAT5 and STAT3 signaling is frequently described in MPN myeloid cells, and constitutive STAT1 signaling has been found in certain cases such as erythroid colonies of ET patients. Negative regulators such as CIS (cytokine-inducible SH2) and SOCS proteins (such as SOCS3) are transcriptionally induced by the activated JAK2 but in general appear to be overwhelmed and cannot efficiently block constitutive JAK2V617F signaling. LNK exerts a negative effect on JAK2V617F signaling and constrains the MPN phenotype. Only a minority of patients have LNK mutations. Activation of RAS signaling is counteracted by NF1 (neurofibromatosis 1), a protein that stimulates the GTPase activity of RAS and that is deleted in a minority of MPN patients. (B) Domain structure of negative signaling regulators LNK, c-CBL, and NF-1. Pro indicates proline-rich domain; PH, plekstrin homology domain; SH2, src-homology 2; TKB, tyrosine kinase binding domain; RING, really interesting new gene finges domain; GRD, GAP (GTPase-activating domain)–related domain; and CRAL-TRIO, cellular retinaldehyde and TRIO domain.