title: Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors.
abstract: The acquisition of growth signal self-sufficiency is 1 of the hallmarks of cancer. We previously reported that the murine interleukin-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3, or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short-term assays. However, resistant clones occur upon long-term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the adenosine triphosphate-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and represent a new mechanism of acquisition of resistance against JAK inhibitors.
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Lorraine
authors.initials: L
authors.lastname: Springuel
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Tekla
authors.initials: T
authors.lastname: Hornakova
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Losdyck
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Fanny
authors.initials: F
authors.lastname: Lambert
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Emilie
authors.initials: E
authors.lastname: Leroy
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.affiliation: Istituto Superiore di Sanità, Rome, Italy; and.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.affiliation: Istituto Superiore di Sanità, Rome, Italy; and.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; Hematology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics*; D053616:Janus Kinase 3 / Q000235:genetics*; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D020125:Mutation, Missense; D009570:Nitriles; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines; D015398:Signal Transduction
chemical_list: D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D000255:Adenosine Triphosphate; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D053612:Janus Kinases