title: JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model.
abstract: JAK3 is a tyrosine kinase that associates with the common γ chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming properties of JAK3 pseudokinase and kinase domain mutants using in vitro and in vivo assays. Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOHITO cell lines to cytokine-independent proliferation. JAK3 pseudokinase mutants were dependent on Jak1 kinase activity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cells in a Jak1 kinase-independent manner. Reconstitution of the IL7 receptor signaling complex in 293T cells showed that JAK3 mutants required receptor binding to mediate downstream STAT5 phosphorylation. Mice transplanted with bone marrow progenitor cells expressing JAK3 mutants developed a long-latency transplantable T-ALL-like disease, characterized by an accumulation of immature CD8(+) T cells. In vivo treatment of leukemic mice with the JAK3 selective inhibitor tofacitinib reduced the white blood cell count and caused leukemic cell apoptosis. Our data show that JAK3 mutations are drivers of T-ALL and require the cytokine receptor complex for transformation. These results warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL.
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Degryse
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Charles E
authors.initials: CE
authors.lastname: de Bock
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Luk
authors.initials: L
authors.lastname: Cox
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Sofie
authors.initials: S
authors.lastname: Demeyer
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Olga
authors.initials: O
authors.lastname: Gielen
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Kris
authors.initials: K
authors.lastname: Jacobs
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Ellen
authors.initials: E
authors.lastname: Geerdens
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;
authors.forename: Valentina
authors.initials: V
authors.lastname: Gianfelici
authors.affiliation: Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Gert
authors.initials: G
authors.lastname: Hulselmans
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Mark
authors.initials: M
authors.lastname: Fiers
authors.affiliation: Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Stein
authors.initials: S
authors.lastname: Aerts
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands; and.
authors.forename: Jules P
authors.initials: JP
authors.lastname: Meijerink
authors.affiliation: Department of Pathology, Universitaire Ziekenhuizen, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease, Leuven, Belgium; Katholieke Universiteit Leuven Center for Human Genetics, Leuven, Belgium;
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
mesh_terms: D000208:Acute Disease; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D053613:Janus Kinase 1 / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009154:Mutation; D010880:Piperidines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053613:Janus Kinase 1; D053616:Janus Kinase 3