In MPNs, dimeric cytokine receptors such as erythropoietin and thrombopoietin receptors are bound by the active JAK2V617F mutant, which endows the receptor with the ability to signal persistently in the absence of or with very low levels of ligands. This results in persistent activation of the indicated downstream pathways, which includes ERK2 (blue). Shown are the 2 substrate-binding domains: the D domain and the DBP domain. Although a small molecule inhibitor (compound #76) blocking the D domain reduces growth of JAK2V617F cells and reduces the MPN phenotype, the inactivation of the DBP domain leads to an enhancement of the MPN phenotype, with progression of PV to MF. ATP, adenosine triphosphate; P, phosphorylation. Professional illustration by Patrick Lane, ScEYEnce Studios.