Tyk2 Mutation Homologous to V617F Jak2 Is Not Found in Essential Thrombocythaemia, Although It Induces Constitutive Signaling and Growth Factor Independence.

A single somatic mutation, V617F, in the pseudokinase domain of the Jak2 is the cause of the majority of polycythaemia vera (PV) cases and one-third of essential thrombocythaemia (ET) cases. PV is characterized by an increase in RBC and erythropoiesis is regulated by erythropoietin (EPO). ET is characterized by the elevation of megakaryopoiesis and platelet numbers, while thrombopoietin (TPO) is a primary regulator of thrombopoiesis. EPO selectively activates Jak2, whereas TPO selectively activates Jak2 and Tyk2. As valine 617 of Jak2 is conserved as valine 678 of Tyk2, we examined the effect of a homologous mutation in Tyk2 (V678F Tyk2) on cell growth. V678F Tyk2 augumented the transcriptional activity of Stat3 and Stat5 in 293T cells. The expression of V678F Tyk2 in Ba/F3 cells induced the phosphorylation of Tyk2 and Stat5 in the absence of cytokine stimulation and induced autonomous cell growth. Ba/F3 cells harboring V678F Tyk2 showed hyper-responsiveness to IL-3. As V678F Tyk2 might cause MPD, we examined the somatic mutation of Tyk2 in 6 ET patients lacking the V617F Jak2 mutation. No cases harbored the Tyk2 mutation. It requires a two-base-pair change to substitute phenylalanine for valine in Tyk2, and the enhancing effects of V678F Tyk2 on cell growth are less dramatic than those of V617F Jak2. The lesser effect of V678F Tyk2 on cell proliferation, together with the lower incidence of VF mutations in Tyk2, might explain why mutations in Tyk2 are rare in ET patients.