title: Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor Specificities.
abstract: JAK1 and JAK3 are recurrently mutated in acute lymphoblastic leukemia. These tyrosine kinases associate with heterodimeric cytokine receptors such as IL-7 receptor or IL-9 receptor, in which JAK1 is appended to the specific chain, and JAK3 is appended to the common gamma chain. Here, we studied the role of these receptor complexes in mediating the oncogenic activity of JAK3 mutants. Although JAK3(V674A) and the majority of other JAK3 mutants needed to bind to a functional cytokine receptor complex to constitutively activate STAT5, JAK3(L857P) was unexpectedly found to not depend on such receptor complexes for its activity, which was induced without receptor or JAK1 co-expression. Introducing a mutation in the FERM domain that abolished JAK-receptor interaction did not affect JAK3(L857P) activity, whereas it inhibited the other receptor-dependent mutants. The same cytokine receptor independence as for JAK3(L857P) was observed for homologous Leu(857) mutations of JAK1 and JAK2 and for JAK3(L875H). This different cytokine receptor requirement correlated with different functional properties in vivo and with distinct sensitivity to JAK inhibitors. Transduction of murine hematopoietic cells with JAK3(V674A) led homogenously to lymphoblastic leukemias in BALB/c mice. In contrast, transduction with JAK3(L857P) induced various types of lymphoid and myeloid leukemias. Moreover, ruxolitinib, which preferentially blocks JAK1 and JAK2, abolished the proliferation of cells transformed by the receptor-dependent JAK3(V674A), yet proved much less potent on cells expressing JAK3(L857P). These particular cells were, in contrast, more sensitive to JAK3-specific inhibitors. Altogether, our results showed that different JAK3 mutations induce constitutive activation through distinct mechanisms, pointing to specific therapeutic perspectives.
authors.affiliation: From the Ludwig Institute for Cancer Research, Brussels Branch and the de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Losdyck
authors.affiliation: From the Ludwig Institute for Cancer Research, Brussels Branch and the de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Tekla
authors.initials: T
authors.lastname: Hornakova
authors.affiliation: From the Ludwig Institute for Cancer Research, Brussels Branch and the de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Springuel
authors.affiliation: the VIB Center for the Biology of Disease, K.U. Leuven, 3000 Leuven, Belgium, the K.U. Leuven Center for Human Genetics, K.U. Leuven, 3000 Leuven, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Degryse
authors.affiliation: the VIB Center for the Biology of Disease, K.U. Leuven, 3000 Leuven, Belgium, the K.U. Leuven Center for Human Genetics, K.U. Leuven, 3000 Leuven, Belgium.
authors.forename: Olga
authors.initials: O
authors.lastname: Gielen
authors.affiliation: the VIB Center for the Biology of Disease, K.U. Leuven, 3000 Leuven, Belgium, the K.U. Leuven Center for Human Genetics, K.U. Leuven, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.affiliation: From the Ludwig Institute for Cancer Research, Brussels Branch and the de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.affiliation: the Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.affiliation: the Genetic Disorders and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesu' IRCCS, Viale di San Paolo 15, 00146 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: From the Ludwig Institute for Cancer Research, Brussels Branch and the de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.affiliation: From the Ludwig Institute for Cancer Research, Brussels Branch and the de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium, the Hematology Unit, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium, and laurent.knoops@uclouvain.be.
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D018121:Receptors, Cytokine; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3
keywords: JAK inhibitor; Janus kinase (JAK); leukemia; oncogene; signal transduction; tyrosine-protein kinase (tyrosine kinase)