Binding of thrombopoietin (TPO) to its receptor (MPL) leads to phosphorylation of JAK2, activation of the JAK-STAT pathway, and increased cellular proliferation (A). JAK2 inhibitors block phosphorylation of JAK2 and reduce cellular proliferation and well as other signaling cascades (B). One mechanism of disease persistence in the setting of JAK2 inhibitor therapy is re-phosphorylation of JAK2 through its heterodimerization with JAK family members JAK1 and TYK2. The result is re-activation of the JAK–STAT pathway and downstream signaling events, including cellular proliferation (C).