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

NPJ Precis Oncol. 2021 Aug 10;5(1):75. doi: 10.1038/s41698-021-00215-x.

Authors

Charlotte E J Downes^{1

2}, Barbara J McClure^{1

3}, John B Bruning⁴, Elyse Page^{1

2}, James Breen^{3

5

6}, Jacqueline Rehn^{1

3}, David T Yeung^{1

3

7}, Deborah L White^{8

9

10

11

12}

Affiliations

¹ Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
² School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
³ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
⁴ Institute of Photonics and Advanced Sensing, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
⁵ Computational and Systems Biology Program, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
⁶ Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
⁷ Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, SA, Australia.
⁸ Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia. deborah.white@sahmri.com.
⁹ School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia. deborah.white@sahmri.com.
¹⁰ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia. deborah.white@sahmri.com.
¹¹ Australian Genomics Health Alliance (AGHA), The Murdoch Children's Research Institute, Parkville, VIC, Australia. deborah.white@sahmri.com.
¹² Australian and New Zealand Children's Oncology Group (ANZCHOG), Clayton, VIC, Australia. deborah.white@sahmri.com.

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.

Abstract

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