Title: Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis
Authors: Tvorogov, D
Thomas, D
Liau, NPD
Dottore, M
Barry, EF
Lathi, M
Kan, WL
Hercus, TR
Stomski, F
Hughes, TP
Tergaonkar, V
Parker, MW
Ross, DM
Majeti, R
Babon, JJ
Lopez, AF
Issue Year: 2018
Publisher AMER ASSOC ADVANCEMENT SCIENCE
Series Sci. Adv.:
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JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn.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 and degradation. In contrast, a type II JAK inhibitor, CHZ868, did not induce JAK2 phosphorylation, was not associated with withdrawal signaling, and was superior in the eradication of flow-purified JAK2(v617F) mutant CD34(+) progenitors after drug washout. Type I inhibitor-induced loop phosphorylation may act as a pathogenic signaling node released upon drug withdrawal, especially in JAK2(v617F) patients.
URI: https://publications.svi.edu.au/publications/4218
Other Identifiers 10.1126/sciadv.aat3834
Publication type Article