Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia ( ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3- independent growth in Ba/F3 cells and/ or IL-9-independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.

Flex, E., Petrangeli, V., Stella, L., Chiaretti, S., Hornakova, T., Knoops, L., et al. (2008). Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. JOURNAL OF EXPERIMENTAL MEDICINE, 205(4), 751-758 [10.1084/jem.20072182].

Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia

STELLA, LORENZO;
2008-01-01

Abstract

Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia ( ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3- independent growth in Ba/F3 cells and/ or IL-9-independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.
2008
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore CHIM/02 - CHIMICA FISICA
English
Con Impact Factor ISI
cyclosporin A; dexamethasone; interleukin 3; interleukin 9; Janus kinase 1; acute lymphoblastic leukemia; adolescent; adult; allele; animal cell; apoptosis; article; child; controlled study; enzyme activity; gene expression; gene function; gene interaction; gene mutation; genetic transcription; human; leukemia cell; leukemogenesis; lymphoma cell; missense mutation; molecular model; mouse; mutational analysis; nonhuman; prevalence; priority journal; prognosis; protein domain; protein localization; signal transduction; T cell lymphoma; T lymphocyte; treatment response; upregulation; Alleles; Animals; Base Sequence; Cell Line, Tumor; DNA Mutational Analysis; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Humans; Janus Kinase 1; Mice; Models, Molecular; Molecular Sequence Data; Mutant Proteins; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma
Flex, E., Petrangeli, V., Stella, L., Chiaretti, S., Hornakova, T., Knoops, L., et al. (2008). Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. JOURNAL OF EXPERIMENTAL MEDICINE, 205(4), 751-758 [10.1084/jem.20072182].
Flex, E; Petrangeli, V; Stella, L; Chiaretti, S; Hornakova, T; Knoops, L; Ariola, C; Fodale, V; Clappier, E; Paoloni, F; Martinelli, S; Fragale, A; Sanchez, M; Tavolaro, S; Messina, M; Cazzaniga, G; Camera, A; Pizzolo, G; Tornesello, A; Vignetti, M; Battistini, A; Cave, H; Gelb, Bd; Renauld, Jc; Biondi, A; Constantinescu, Sn; Foa, R; Tartaglia, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/30866
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