Reference Detail

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.
Journal PloS one
Vol 7
Issue 8
Date 2012
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 Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
E864K missense gain of function - predicted JAK2 E864K lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). E864K is predicted to confer a gain of function to the Jak2 protein, as demonstrated by increased Jak2 and Stat5 phosphorylation and also prevents apoptosis in the presence of a Jak inhibitor (PMID: 22916261) and therefore, has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22916261, PMID: 22271575). Y
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, Apr 2019). Y
G935R missense gain of function - predicted JAK2 G935R lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). G935R is predicted to confer a gain of function to the Jak2 protein, as demonstrated by increased Jak2 and Stat5 phosphorylation and also prevents apoptosis in the presence of a Jak inhibitor (PMID: 22916261) and therefore, has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22271575, PMID: 22916261). Y
M929I missense gain of function - predicted JAK2 M929I is a gatekeeper mutation that lies within the protein kinase 2 domain of the Jak2 protein (PMID: 22916261, PMID: 23823659). M929I is predicted to confer a gain of function to the Jak2 protein as demonstrated by increased Jak2 and Stat5 phosphorylation (PMID: 22916261), and has also been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22916261, PMID: 23823659, PMID: 21926964). Y
N909K missense gain of function - predicted JAK2 N909K lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). N909K is predicted to confer a gain of function to the Jak2 protein, as demonstrated by 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). Y
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, Apr 2019). Y
R975G missense gain of function - predicted JAK2 R975G lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). R975G is predicted to confer a gain of function to the Jak2 protein, as demonstrated by 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). Y
V881A missense gain of function - predicted JAK2 V881A lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). V881A is predicted to confer a gain of function to the Jak2 protein, as demonstrated by 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). Y
Y918H missense unknown JAK2 Y918H lies within the 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, Apr 2019). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ETV6 - JAK2 JAK2 P1057S hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the P1057S mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6-JAK2 JAK2 R975G hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the R975G mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6-JAK2 JAK2 N909K hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the N909K mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6 - JAK2 JAK2 Y918H hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the Y918H mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6 - JAK2 JAK2 G935R hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the G935R mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6 - JAK2 JAK2 E864K hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the E864K mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6-JAK2 JAK2 V881A hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the V881A mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6 - JAK2 JAK2 R1127K hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the R1127K mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6 - JAK2 JAK2 G831R hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the G831R mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261
ETV6 - JAK2 JAK2 M929I hematologic cancer resistant Pyridone 6 Preclinical Actionable In a preclinical study, immune cells expressing ETV6-JAK2 with the M929I mutation demonstrated resistance to Pyridone 6 (CMP6) in culture (PMID: 22916261). 22916261