Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/131680
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Type: Journal article
Title: Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia
Author: Downes, C.E.J.
McClure, B.J.
Bruning, J.B.
Page, E.
Breen, J.
Rehn, J.
Yeung, D.T.
White, D.L.
Citation: npj Precision Oncology, 2021; 5(1):1-13
Publisher: Nature Research (part of Springer Nature)
Issue Date: 2021
ISSN: 2397-768X
2397-768X
Statement of
Responsibility: 
Charlotte E. J. Downes, Barbara J. McClure, John B. Bruning, Elyse Page, James Breen, Jacqueline Rehn ... et al.
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.
Rights: © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
DOI: 10.1038/s41698-021-00215-x
Grant ID: http://purl.org/au-research/grants/nhmrc/1044884
http://purl.org/au-research/grants/nhmrc/1057746
Published version: http://dx.doi.org/10.1038/s41698-021-00215-x
Appears in Collections:Aurora harvest 4
Environment Institute publications

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