Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia

Abstract Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance in JAK2r B-...

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Autores principales:	Charlotte E. J. Downes, Barbara J. McClure, John B. Bruning, Elyse Page, James Breen, Jacqueline Rehn, David T. Yeung, Deborah L. White
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/7fa4c9c585af412ca5bde1562f25caaf
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spelling	oai:doaj.org-article:7fa4c9c585af412ca5bde1562f25caaf2021-12-02T16:43:41ZAcquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia10.1038/s41698-021-00215-x2397-768Xhttps://doaj.org/article/7fa4c9c585af412ca5bde1562f25caaf2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00215-xhttps://doaj.org/toc/2397-768XAbstract Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. We generated a murine pro-B cell model of ATF7IP-JAK2 with acquired resistance to multiple type-I JAK inhibitors. Resistance was associated with mutations within the JAK2 ATP/rux binding site, including a JAK2 p.G993A mutation. Using in vitro models of JAK2r B-ALL, JAK2 p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate that JAK2 p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort.Charlotte E. J. DownesBarbara J. McClureJohn B. BruningElyse PageJames BreenJacqueline RehnDavid T. YeungDeborah L. WhiteNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Charlotte E. J. Downes Barbara J. McClure John B. Bruning Elyse Page James Breen Jacqueline Rehn David T. Yeung Deborah L. White Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia
description	Abstract Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. We generated a murine pro-B cell model of ATF7IP-JAK2 with acquired resistance to multiple type-I JAK inhibitors. Resistance was associated with mutations within the JAK2 ATP/rux binding site, including a JAK2 p.G993A mutation. Using in vitro models of JAK2r B-ALL, JAK2 p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate that JAK2 p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort.
format	article
author	Charlotte E. J. Downes Barbara J. McClure John B. Bruning Elyse Page James Breen Jacqueline Rehn David T. Yeung Deborah L. White
author_facet	Charlotte E. J. Downes Barbara J. McClure John B. Bruning Elyse Page James Breen Jacqueline Rehn David T. Yeung Deborah L. White
author_sort	Charlotte E. J. Downes
title	Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia
title_short	Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia
title_full	Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia
title_fullStr	Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia
title_full_unstemmed	Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia
title_sort	acquired jak2 mutations confer resistance to jak inhibitors in cell models of acute lymphoblastic leukemia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7fa4c9c585af412ca5bde1562f25caaf
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Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia

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