biostudies-literatureMarit MRCanadian Institutes of Health Researche43437https://www.ebi.ac.uk/biostudies/studies/S-EPMC3420867biostudies-literatureUnknown7(8)<h4>Background</h4>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.<h4>Methodology</h4>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 mutatPloS oneRandom mutagenesis reveals residues of JAK2 critical in evading inhibition by a tyrosine kinase inhibitor.PMC3420867FRN-42428FRN-79400Marit MRChohan MMatthew NKuntz DARose DRBarber DLHuang KfalseRandom mutagenesis reveals residues of JAK2 critical in evading inhibition by a tyrosine kinase inhibitor.<h4>Background</h4>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.<h4>Methodology</h4>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 mutat2012-01-01T00:00:00Z20122026-04-18T09:10:59.766Z2026-04-07T14:35:34.546ZS-EPMC34208672291626110.1371/journal.pone.0043437