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

Charlotte E. J. Downes; Barbara J. McClure; John B. Bruning; Elyse Page; James Breen; Jacqueline Rehn; David T. Yeung; Deborah L. White

doi:10.1038/s41698-021-00215-x

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

Charlotte E. J. Downes, Barbara J. McClure, John B. Bruning, Elyse Page, James Breen, Jacqueline Rehn, David T. Yeung, Deborah L. White

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	75
Number of pages	13
Journal	npj Precision Oncology
Volume	5
DOIs	https://doi.org/10.1038/s41698-021-00215-x
Publication status	Published - 10 Aug 2021
Externally published	Yes

Keywords

Acute lymphocytic leukaemia
Cancer therapeutic resistance
Targeted therapies

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41698-021-00215-xLicence: CC BY

Final published versionFinal published version, 2.49 MBLicence: CC BY

Cite this

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title = "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-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.",

keywords = "Acute lymphocytic leukaemia, Cancer therapeutic resistance, Targeted therapies",

author = "Downes, {Charlotte E. J.} and McClure, {Barbara J.} and Bruning, {John B.} and Elyse Page and James Breen and Jacqueline Rehn and Yeung, {David T.} and White, {Deborah L.}",

year = "2021",

month = aug,

day = "10",

doi = "10.1038/s41698-021-00215-x",

language = "English",

volume = "5",

journal = "npj Precision Oncology",

issn = "2397-768X",

publisher = "Springer Nature",

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TY - JOUR

T1 - Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia

AU - Downes, Charlotte E. J.

AU - McClure, Barbara J.

AU - Bruning, John B.

AU - Page, Elyse

AU - Breen, James

AU - Rehn, Jacqueline

AU - Yeung, David T.

AU - White, Deborah L.

PY - 2021/8/10

Y1 - 2021/8/10

N2 - 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.

AB - 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.

KW - Acute lymphocytic leukaemia

KW - Cancer therapeutic resistance

KW - Targeted therapies

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UR - http://purl.org/au-research/grants/NHMRC/1057746

U2 - 10.1038/s41698-021-00215-x

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ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Identification of ruxolitinib resistance mutations in Pro-B cells driven by a high-risk B-ALL JAK2-fusion

Acquired mutations within the JAK2 kinase domain confer resistance to JAK inhibitors in in vitro models of a high-risk acute lymphoblastic leukaemia

Acquired Mutations within the JAK2 Kinase Domain confer Resistance to JAK Inhibitors in in vitro Models of High-Risk ALL

Acquired Mutations within the JAK2 Kinase Domain Confer Resistance to JAK Inhibitors in an in Vitro model of a High-Risk Acute Lymphoblastic Leukemia

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Activities

Identification of ruxolitinib resistance mutations in Pro-B cells driven by a high-risk B-ALL JAK2-fusion

Research output

Acquired mutations within the JAK2 kinase domain confer resistance to JAK inhibitors in in vitro models of a high-risk acute lymphoblastic leukaemia

Acquired Mutations within the JAK2 Kinase Domain confer Resistance to JAK Inhibitors in in vitro Models of High-Risk ALL

Acquired Mutations within the JAK2 Kinase Domain Confer Resistance to JAK Inhibitors in an in Vitro model of a High-Risk Acute Lymphoblastic Leukemia

Cite this