Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy

Priya Koppikar, Neha Bhagwat, Outi Kilpivaara, Taghi Manshouri, Mazhar Adli, Todd Hricik, Fan Liu, Lindsay M. Saunders, Ann Mullally, Omar Abdel-Wahab, Laura Leung, Abby Weinstein, Sachie Marubayashi, Aviva Goel, Mithat Gonen, Zeev Estrov, Benjamin L. Ebert, Gabriela Chiosis, Stephen D. Nimer, Bradley E. BernsteinSrdan Verstovsek, Ross L. Levine

Research output: Contribution to journalArticle

213 Scopus citations

Abstract

The identification of somatic activating mutations in JAK2 (refsĝ€‰1ĝ€"4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAKĝ€"STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.

Original languageEnglish (US)
Pages (from-to)155-159
Number of pages5
JournalNature
Volume489
Issue number7414
DOIs
StatePublished - Sep 6 2012

ASJC Scopus subject areas

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    Koppikar, P., Bhagwat, N., Kilpivaara, O., Manshouri, T., Adli, M., Hricik, T., Liu, F., Saunders, L. M., Mullally, A., Abdel-Wahab, O., Leung, L., Weinstein, A., Marubayashi, S., Goel, A., Gonen, M., Estrov, Z., Ebert, B. L., Chiosis, G., Nimer, S. D., ... Levine, R. L. (2012). Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature, 489(7414), 155-159. https://doi.org/10.1038/nature11303