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Type: Journal article
Title: Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis
Author: Tvorogov, D.
Thomas, D.
Liau, N.
Dottore, M.
Barry, E.
Lathi, M.
Kan, W.
Hercus, T.
Stomski, F.
Hughes, T.
Tergaonkar, V.
Parker, M.
Ross, D.
Majeti, R.
Babon, J.
Lopez, A.
Citation: Science Advances, 2018; 4(11):1-12
Publisher: American Association for the Advancement of Science
Issue Date: 2018
ISSN: 2375-2548
Statement of
Denis Tvorogov, Daniel Thomas, Nicholas P.D. Liau, Mara Dottore, Emma F. Barry, Maya Lathi, Winnie L. Kan, Timothy R. Hercus, Frank Stomski, Timothy P. Hughes, Vinay Tergaonkar, Michael W. Parker, David M. Ross, Ravindra Majeti, Jeffrey J. Babon, Angel F. Lopez
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JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn.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 JAK2V617F and CALR mutant myelofibrosis patient samples and observed notable activation of spontaneous STAT signaling in JAK2V617F samples after drug washout. Accumulation of ruxolitinib-induced JAK2 phosphorylation was dose dependent and correlated with rebound signaling and the presence of a JAK2V617F mutation. Ruxolitinib prevented dephosphorylation of a cryptic site involving Tyr1007/1008 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 JAK2V617F 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 JAK2V617F patients.
Keywords: Tumor Cells, Cultured; Humans; Substance Withdrawal Syndrome; Pyrazoles; Signal Transduction; Apoptosis; Cell Proliferation; Phosphorylation; Mutation; Janus Kinase 2; Primary Myelofibrosis; Janus Kinase Inhibitors
Rights: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
RMID: 0030105134
DOI: 10.1126/sciadv.aat3834
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Appears in Collections:Medicine publications

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