We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia.
- Authors
Zenatti, Priscila P; Ribeiro, Daniel; Li, Wenqing; Zuurbier, Linda; Silva, Milene C; Paganin, Maddalena; Tritapoe, Julia; Hixon, Julie A; Silveira, André B; Cardoso, Bruno A; Sarmento, Leonor M; Correia, Nádia; Toribio, Maria L; Kobarg, Jörg; Horstmann, Martin; Pieters, Rob; Brandalise, Silvia R; Ferrando, Adolfo A; Meijerink, Jules P; Durum, Scott K
- Abstract
Interleukin 7 (IL-7) and its receptor, formed by IL-7R? (encoded by IL7R) and ?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-7R? subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, ?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.
- Subjects
ONCOGENES; LYMPHOBLASTIC leukemia in children; T cells; HOMEOSTASIS; EXONS (Genetics); INTERMOLECULAR forces; CELL transformation; GENETICS
- Publication
Nature Genetics, 2011, Vol 43, Issue 10, p932
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.924