Distinct acute lymphoblastic leukemia (ALL)-associated Janus Kinase 3 (JAK3) mutants exhibit different cytokine-receptor requirements and JAK-inhibitor specificities
| Autor: | Jean-Christophe Renauld, Elisabetta Flex, Sandrine Degryse, Jan Cools, Laurent Knoops, Tekla Hornakova, Marco Tartaglia, Elisabeth Losdyck, Stefan N. Constantinescu, Olga Gielen, Lorraine Springuel |
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| Přispěvatelé: | UCL - (SLuc) Service d'hématologie, UCL - SSS/DDUV - Institut de Duve |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Mutation
Missense Tyrosine-protein kinase (tyrosine kinase) Biology Signal transduction Biochemistry Mice hemic and lymphatic diseases Cell Line Tumor CD135 Animals Humans Receptors Cytokine Receptor Molecular Biology Protein Kinase Inhibitors Oncogene Common gamma chain Mice Inbred BALB C Leukemia Janus kinase 3 Janus kinase (JAK) Janus Kinase 3 Cell Biology Janus Kinase 1 Janus Kinase 2 Precursor Cell Lymphoblastic Leukemia-Lymphoma Molecular biology Neoplasm Proteins Amino Acid Substitution JAK inhibitor Interleukin-21 receptor Cancer research Cytokine receptor Tyrosine kinase Signal Transduction |
| Zdroj: | Journal of Biological Chemistry, Vol. 290, no. 48, p. 29022-29034 (2015) |
| Popis: | 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. ispartof: Journal of Biological Chemistry vol:290 issue:48 pages:29022-34 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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