Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis
- Author(s)
- 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;
- Details
- Publication Year 2018-11,Volume 4,Issue #11,Page eaat3834
- Journal Title
- Scientific Advances
- Publication Type
- Journal Article
- 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JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn.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.
- Publisher
- AAAS
- Research Division(s)
- Structural Biology
- PubMed ID
- 30498775
- Publisher's Version
- https://doi.org/10.1126/sciadv.aat3834
- Open Access at Publisher's Site
https://doi.org/10.1126/sciadv.aat3834- Terms of Use/Rights Notice
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Creation Date: 2018-12-18 02:54:32
Last Modified: 2018-12-18 04:13:06