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Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy
The identification of somatic activating mutations in JAK2(1–4) and in the thrombopoietin receptor (MPL)(5) in the majority of myeloproliferative neoplasm (MPN) patients led to the clinical development of JAK2 kinase inhibitors(6,7). JAK2 inhibitor therapy improves MPN-associated splenomegaly and sy...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991463/ https://www.ncbi.nlm.nih.gov/pubmed/22820254 http://dx.doi.org/10.1038/nature11303 |
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author | Koppikar, Priya Bhagwat, Neha Kilpivaara, Outi Manshouri, Taghi Adli, Mazhar Hricik, Todd Liu, Fan Saunders, Lindsay M. Mullally, Ann Abdel-Wahab, Omar Leung, Laura Weinstein, Abby Marubayashi, Sachie Goel, Aviva Gönen, Mithat Estrov, Zeev Ebert, Benjamin L. Chiosis, Gabriela Nimer, Stephen D. Bernstein, Bradley E. Verstovsek, Srdan Levine, Ross L. |
author_facet | Koppikar, Priya Bhagwat, Neha Kilpivaara, Outi Manshouri, Taghi Adli, Mazhar Hricik, Todd Liu, Fan Saunders, Lindsay M. Mullally, Ann Abdel-Wahab, Omar Leung, Laura Weinstein, Abby Marubayashi, Sachie Goel, Aviva Gönen, Mithat Estrov, Zeev Ebert, Benjamin L. Chiosis, Gabriela Nimer, Stephen D. Bernstein, Bradley E. Verstovsek, Srdan Levine, Ross L. |
author_sort | Koppikar, Priya |
collection | PubMed |
description | The identification of somatic activating mutations in JAK2(1–4) and in the thrombopoietin receptor (MPL)(5) in the majority of myeloproliferative neoplasm (MPN) patients led to the clinical development of JAK2 kinase inhibitors(6,7). JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms, but does not significantly reduce or eliminate the MPN clone in most MPN patients. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic JAK2 inhibition. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signaling and with heterodimerization between activated JAK2 and JAK1/TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible, such that 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, murine models, and patients treated with JAK2 inhibitors. RNA interference and pharmacologic studies demonstrate 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. |
format | Online Article Text |
id | pubmed-3991463 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
record_format | MEDLINE/PubMed |
spelling | pubmed-39914632014-04-18 Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy Koppikar, Priya Bhagwat, Neha Kilpivaara, Outi Manshouri, Taghi Adli, Mazhar Hricik, Todd Liu, Fan Saunders, Lindsay M. Mullally, Ann Abdel-Wahab, Omar Leung, Laura Weinstein, Abby Marubayashi, Sachie Goel, Aviva Gönen, Mithat Estrov, Zeev Ebert, Benjamin L. Chiosis, Gabriela Nimer, Stephen D. Bernstein, Bradley E. Verstovsek, Srdan Levine, Ross L. Nature Article The identification of somatic activating mutations in JAK2(1–4) and in the thrombopoietin receptor (MPL)(5) in the majority of myeloproliferative neoplasm (MPN) patients led to the clinical development of JAK2 kinase inhibitors(6,7). JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms, but does not significantly reduce or eliminate the MPN clone in most MPN patients. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic JAK2 inhibition. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signaling and with heterodimerization between activated JAK2 and JAK1/TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible, such that 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, murine models, and patients treated with JAK2 inhibitors. RNA interference and pharmacologic studies demonstrate 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. 2012-09-06 /pmc/articles/PMC3991463/ /pubmed/22820254 http://dx.doi.org/10.1038/nature11303 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Koppikar, Priya Bhagwat, Neha Kilpivaara, Outi Manshouri, Taghi Adli, Mazhar Hricik, Todd Liu, Fan Saunders, Lindsay M. Mullally, Ann Abdel-Wahab, Omar Leung, Laura Weinstein, Abby Marubayashi, Sachie Goel, Aviva Gönen, Mithat Estrov, Zeev Ebert, Benjamin L. Chiosis, Gabriela Nimer, Stephen D. Bernstein, Bradley E. Verstovsek, Srdan Levine, Ross L. Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy |
title | Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy |
title_full | Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy |
title_fullStr | Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy |
title_full_unstemmed | Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy |
title_short | Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy |
title_sort | heterodimeric jak-stat activation as a mechanism of persistence to jak2 inhibitor therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991463/ https://www.ncbi.nlm.nih.gov/pubmed/22820254 http://dx.doi.org/10.1038/nature11303 |
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