Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis.

ABSTRACT: Treatment of patients with myelofibrosis with the type I JAK (Janus kinase) inhibitor ruxolitinib paradoxically induces JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn. We developed a time-dependent assay to mimic ruxolitinib withdrawal in primary JAK2^V617F and CALR mutant myelofibrosis patient samples and observed notable activation of spontaneous STAT signaling in JAK2^V617F samples after drug washout. Accumulation of ruxolitinib-induced JAK2 phosphorylation was dose dependent and correlated with rebound signaling and the presence of a JAK2^V617F mutation. Ruxolitinib prevented dephosphorylation of a cryptic site involving Tyr^1007/1008 in JAK2 blocking ubiquitination an

SUBMITTER: Tvorogov D 

PROVIDER: S-EPMC6261652 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature