Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
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
_version_ 1782312442527744000
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
work_keys_str_mv AT koppikarpriya heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT bhagwatneha heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT kilpivaaraouti heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT manshouritaghi heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT adlimazhar heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT hriciktodd heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT liufan heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT saunderslindsaym heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT mullallyann heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT abdelwahabomar heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT leunglaura heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT weinsteinabby heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT marubayashisachie heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT goelaviva heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT gonenmithat heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT estrovzeev heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT ebertbenjaminl heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT chiosisgabriela heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT nimerstephend heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT bernsteinbradleye heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT verstovseksrdan heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy
AT levinerossl heterodimericjakstatactivationasamechanismofpersistencetojak2inhibitortherapy