Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia

Priscila P. Zenatti, Daniel Ribeiro, Wenqing Li, Linda Zuurbier, Milene C. Silva, Maddalena Paganin, Julia Tritapoe, Julie A. Hixon, André B. Silveira, Bruno A. Cardoso, Leonor M. Sarmento, Nádia Correia, Maria L. Toribio, Jörg Kobarg, Martin Horstmann, Rob Pieters, Silvia R. Brandalise, Adolfo A. Ferrando, Jules P. Meijerink, Scott K. DurumJ. Andrés Yunes, João T. Barata

Research output: Contribution to journalArticlepeer-review

328 Citations (Scopus)

Abstract

Interleukin 7 (IL-7) and its receptor, formed by IL-7Rα (encoded by IL7R) and γc, 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-7Rα subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, γc 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.

Original languageEnglish
Pages (from-to)932-941
Number of pages10
JournalNature Genetics
Volume43
Issue number10
DOIs
Publication statusPublished - Oct 2011
Externally publishedYes

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