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Ref Type Journal Article
PMID (22916261)
Authors Marit MR, Chohan M, Matthew N, Huang K, Kuntz DA, Rose DR, Barber DL
Title Random mutagenesis reveals residues of JAK2 critical in evading inhibition by a tyrosine kinase inhibitor.
URL
Abstract Text The non-receptor tyrosine kinase JAK2 is implicated in a group of myeloproliferative neoplasms including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2-selective inhibitors are currently being evaluated in clinical trials. Data from drug-resistant chronic myeloid leukemia patients demonstrate that treatment with a small-molecule inhibitor generates resistance via mutation or amplification of BCR-ABL. We hypothesize that treatment with small molecule inhibitors of JAK2 will similarly generate inhibitor-resistant mutants in JAK2.In order to identify inhibitor-resistant JAK2 mutations a priori, we utilized TEL-JAK2 to conduct an in vitro random mutagenesis screen for JAK2 alleles resistant to JAK Inhibitor-I. Isolated mutations were evaluated for their ability to sustain cellular growth, stimulate downstream signaling pathways, and phosphorylate a novel JAK2 substrate in the presence of inhibitor.Mutations were found exclusively in the kinase domain of JAK2. The panel of mutations conferred resistance to high concentrations of inhibitor accompanied by sustained activation of the Stat5, Erk1/2, and Akt pathways. Using a JAK2 substrate, enhanced catalytic activity of the mutant JAK2 kinase was observed in inhibitor concentrations 200-fold higher than is inhibitory to the wild-type protein. When testing the panel of mutations in the context of the Jak2 V617F allele, we observed that a subset of mutations conferred resistance to inhibitor, validating the use of TEL-JAK2 in the initial screen. These results demonstrate that small-molecule inhibitors select for JAK2 inhibitor-resistant alleles, and the design of next-generation JAK2 inhibitors should consider the location of mutations arising in inhibitor-resistant screens.

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Molecular Profile Treatment Approach
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 E864K missense gain of function - predicted JAK2 E864K lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). E864K results in increased Jak2 and Stat5 phosphorylation and prevents apoptosis in the presence of a Jak inhibitor (PMID: 22916261), and has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22916261, PMID: 22271575), and therefore, is predicted to lead to a gain of Jak2 protein function. Y
JAK2 G831R missense unknown JAK2 G831R does not lie within any known functional domains of the Jak2 protein (UniProt.org). G831R has been demonstrated to occur as a secondary drug resistance mutation (PMID: 22916261), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Nov 2023). Y
JAK2 G935R missense gain of function - predicted JAK2 G935R lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). G935R results in increased Jak2 and Stat5 phosphorylation, prevents apoptosis in the presence of a Jak inhibitor (PMID: 22916261), and has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22271575, PMID: 22916261), and therefore, is predicted to lead to a gain of Jak2 protein function. Y
JAK2 M929I missense gain of function - predicted JAK2 M929I is a gatekeeper mutation that lies within protein kinase domain 2 of the Jak2 protein (PMID: 22916261, PMID: 23823659). M929I demonstrates increased Jak2 and Stat5 phosphorylation (PMID: 22916261), and has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22916261, PMID: 23823659, PMID: 21926964), and therefore, is predicted to lead to a gain of Jak2 protein function. Y
JAK2 N909K missense gain of function - predicted JAK2 N909K lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). N909K results in increased Jak2, Stat5, Akt and Erk phosphorylation, and has also been described as a secondary drug resistance mutation in the context of ETV6-JAK2 (PMID: 22916261), and therefore, is predicted to lead to a gain of Jak2 protein function. Y
JAK2 P1057S missense unknown JAK2 P1057S lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). P1057S has been demonstrated to occur as a secondary drug resistance mutation (PMID: 22916261), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Nov 2023). Y
JAK2 R1127K missense unknown JAK2 R1127K does not lie within any known functional domains of the Jak2 protein (UniProt.org). R1127K has been demonstrated to occur as a secondary drug resistance mutation (PMID: 22916261), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Nov 2023). Y
JAK2 R975G missense gain of function - predicted JAK2 R975G lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). R975G results in increased Jak2, Stat5, Akt and Erk phosphorylation, and has also been described as a secondary drug resistance mutation in the context of ETV6-JAK2 (PMID: 22916261), and therefore, is predicted to lead to a gain of Jak2 protein function. Y
JAK2 V881A missense gain of function - predicted JAK2 V881A lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). V881A results in increased Jak2, Stat5, Akt and Erk phosphorylation, and has also been described as a secondary drug resistance mutation in the context of ETV6-JAK2 (PMID: 22916261), and therefore, is predicted to lead to a gain of Jak2 protein function. Y
JAK2 Y918H missense unknown JAK2 Y918H lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). Y918H has been demonstrated to occur as a secondary drug resistance mutation (PMID: 22916261), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Nov 2023). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References