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Ref Type Journal Article
PMID (34376782)
Authors Downes CEJ, McClure BJ, Bruning JB, Page E, Breen J, Rehn J, Yeung DT, White DL
Title Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia.
Journal Vol Issue Date Pages Journal Short Title
NPJ precision oncology 5 1 2021 Aug 10 75 NPJ Precis Oncol
URL
Abstract Text 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.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK2 G993A missense unknown JAK2 G993A lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). G993A has been demonstrated to occur as a secondary drug resistance mutation in the context of JAK2 fusions in cultured cells (PMID: 34376782), and is not transforming in culture (PMID: 34376782), but has not been fully biochemically characterized and therefore, its effect on Jak2 protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References