Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/81740
Type: Artigo de periódico
Title: Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia
Author: Zenatti, PP
Ribeiro, D
Li, WQ
Zuurbier, L
Silva, MC
Paganin, M
Tritapoe, J
Hixon, JA
Silveira, AB
Cardoso, BA
Sarmento, LM
Correia, N
Toribio, ML
Kobarg, J
Horstmann, M
Pieters, R
Brandalise, SR
Ferrando, AA
Meijerink, JP
Durum, SK
Yunes, JA
Barata, JT
Abstract: Interleukin 7 (IL-7) and its receptor, formed by IL-7R alpha (encoded by IL7R) and gamma c, are essential for normal T-cell development and homeostasis. Here we show that IL7R is an oncogene mutated in T-cell acute lymphoblastic leukemia (T-ALL). We find that 9% of individuals with T-ALL have somatic gain-of-function IL7R exon 6 mutations. In most cases, these IL7R mutations introduce an unpaired cysteine in the extracellular juxtamembrane-transmembrane region and promote de novo formation of intermolecular disulfide bonds between mutant IL-7Ra subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, gamma c or JAK3. IL7R mutations induce a gene expression profile partially resembling that provoked by IL-7 and are enriched in the T-ALL subgroup comprising TLX3 rearranged and HOXA deregulated cases. Notably, IL7R mutations promote cell transformation and tumor formation. Overall, our findings indicate that IL7R mutational activation is involved in human T-cell leukemogenesis, paving the way for therapeutic targeting of IL-7R-mediated signaling in T-ALL.
Country: EUA
Editor: Nature Publishing Group
Rights: fechado
Identifier DOI: 10.1038/ng.924
Date Issue: 2011
Appears in Collections:Unicamp - Artigos e Outros Documentos

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