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

Denis Tvorogov, Daniel Thomas, Nicholas P.D. Liau, Mara Dottore, Emma F. Barry, Maya Lathi, Winnie L. Kan, Timothy R. Hercus, Frank Stomski, Timothy Hughes, Vinay Tergaonkar, Michael W. Parker, David M. Ross, Ravindra Majeti, Jeffrey J. Babon, Angel F. Lopez

Research output: Contribution to journalArticle

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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JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn.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.

LanguageEnglish
Article numbereaat3834
JournalScience Advances
Volume4
Issue number11
DOIs
Publication statusPublished - 28 Nov 2018

ASJC Scopus subject areas

  • General

Cite this

Tvorogov, Denis ; Thomas, Daniel ; Liau, Nicholas P.D. ; Dottore, Mara ; Barry, Emma F. ; Lathi, Maya ; Kan, Winnie L. ; Hercus, Timothy R. ; Stomski, Frank ; Hughes, Timothy ; Tergaonkar, Vinay ; Parker, Michael W. ; Ross, David M. ; Majeti, Ravindra ; Babon, Jeffrey J. ; Lopez, Angel F. / Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis. In: Science Advances. 2018 ; Vol. 4, No. 11.
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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.",
author = "Denis Tvorogov and Daniel Thomas and Liau, {Nicholas P.D.} and Mara Dottore and Barry, {Emma F.} and Maya Lathi and Kan, {Winnie L.} and Hercus, {Timothy R.} and Frank Stomski and Timothy Hughes and Vinay Tergaonkar and Parker, {Michael W.} and Ross, {David M.} and Ravindra Majeti and Babon, {Jeffrey J.} and Lopez, {Angel F.}",
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Tvorogov, D, Thomas, D, Liau, NPD, Dottore, M, Barry, EF, Lathi, M, Kan, WL, Hercus, TR, Stomski, F, Hughes, T, Tergaonkar, V, Parker, MW, Ross, DM, Majeti, R, Babon, JJ & Lopez, AF 2018, 'Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis', Science Advances, vol. 4, no. 11, eaat3834. https://doi.org/10.1126/sciadv.aat3834

Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis. / Tvorogov, Denis; Thomas, Daniel; Liau, Nicholas P.D.; Dottore, Mara; Barry, Emma F.; Lathi, Maya; Kan, Winnie L.; Hercus, Timothy R.; Stomski, Frank; Hughes, Timothy; Tergaonkar, Vinay; Parker, Michael W.; Ross, David M.; Majeti, Ravindra; Babon, Jeffrey J.; Lopez, Angel F.

In: Science Advances, Vol. 4, No. 11, eaat3834, 28.11.2018.

Research output: Contribution to journalArticle

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T1 - Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis

AU - Tvorogov, Denis

AU - Thomas, Daniel

AU - Liau, Nicholas P.D.

AU - Dottore, Mara

AU - Barry, Emma F.

AU - Lathi, Maya

AU - Kan, Winnie L.

AU - Hercus, Timothy R.

AU - Stomski, Frank

AU - Hughes, Timothy

AU - Tergaonkar, Vinay

AU - Parker, Michael W.

AU - Ross, David M.

AU - Majeti, Ravindra

AU - Babon, Jeffrey J.

AU - Lopez, Angel F.

PY - 2018/11/28

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DO - 10.1126/sciadv.aat3834

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