title: Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia.
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.
authors: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, 00161, Italy.
authors: Elisabetta
authors: E
authors: Flex
authors: Valentina
authors: V
authors: Petrangeli
authors: Lorenzo
authors: L
authors: Stella
authors: Sabina
authors: S
authors: Chiaretti
authors: Tekla
authors: T
authors: Hornakova
authors: Laurent
authors: L
authors: Knoops
authors: Cristina
authors: C
authors: Ariola
authors: Valentina
authors: V
authors: Fodale
authors: Emmanuelle
authors: E
authors: Clappier
authors: Francesca
authors: F
authors: Paoloni
authors: Simone
authors: S
authors: Martinelli
authors: Alessandra
authors: A
authors: Fragale
authors: Massimo
authors: M
authors: Sanchez
authors: Simona
authors: S
authors: Tavolaro
authors: Monica
authors: M
authors: Messina
authors: Giovanni
authors: G
authors: Cazzaniga
authors: Andrea
authors: A
authors: Camera
authors: Giovanni
authors: G
authors: Pizzolo
authors: Assunta
authors: A
authors: Tornesello
authors: Marco
authors: M
authors: Vignetti
authors: Angela
authors: A
authors: Battistini
authors: Hélène
authors: H
authors: Cavé
authors: Bruce D
authors: BD
authors: Gelb
authors: Jean-Christophe
authors: JC
authors: Renauld
authors: Andrea
authors: A
authors: Biondi
authors: Stefan N
authors: SN
authors: Constantinescu
authors: Robin
authors: R
authors: Foà
authors: Marco
authors: M
authors: Tartaglia
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
chemical_list: D050505:Mutant Proteins; D053613:Janus Kinase 1