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.
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We are grateful to the subjects and their families for providing the specimens for this study. We thank S. Walsh (University of Maryland) for helpful discussions on the IL7R transmembrane domain; K. Czarra and M. Karwan for animal technical assistance; A. Silva, I. Antunes, A. Melão and J. Buijs-Gladdines for experimental support; P. Vandenabeele for kindly providing the WEHI3B cell line; and J. O'Shea for providing Jak3−/− bone marrow and CP-690550. This work was supported by grants from Fundação para a Ciência e a Tecnologia (FCT; PTDC/SAU-OBD/104816/2008, J.T.B.), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 08/10034-1, J.A.Y.) and the intramural program of the National Cancer Institute, US National Institutes of Health (NIH) (S.K.D.). P.P.Z. and A.B.S. have Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) PhD scholarships. L.M.S. has a postdoctoral fellowship; D.R., B.A.C. and N.C. have PhD scholarships, and M.C.S. had a Bolsa de Investigação (BI) fellowship, all from the FCT. L.Z. was supported by a grant (2007-012) from the foundation Children Cancer-Free (Stichting Kinderen Kankervrij; KiKa).
The authors declare no competing financial interests.
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Zenatti, P., Ribeiro, D., Li, W. et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet 43, 932–939 (2011) doi:10.1038/ng.924
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