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

Nature Genetics volume 43, pages 932–939 (2011)Cite this article

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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.

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Figure 1: IL7R exon 6 somatic mutations in pediatric T-ALL.
Figure 2: Molecular signatures associated with IL7R mutations in T-ALL.
Figure 3: IL7R mutations induce constitutive signaling in a manner that is independent of IL-7, γc and JAK3 and relies on disulfide bond promotion of homodimer formation.
Figure 4: IL7R mutations induce cell-cycle progression, increase cell viability and promote growth factor independence.
Figure 5: In vivo tumorigenic effect of IL7R mutations.
Figure 6: Targeting IL7R mutants using JAK-STAT pathway inhibitors.

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Acknowledgements

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).

Author information

Author notes

  1. Priscila P Zenatti, Daniel Ribeiro and Wenqing Li: These authors contributed equally to this work.

  2. J Andrés Yunes and João T Barata: These authors jointly directed this work.

Authors and Affiliations

  1. Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, São Paulo, Brazil.,

    Priscila P Zenatti, André B Silveira, Silvia R Brandalise & J Andrés Yunes

  2. Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal

    Daniel Ribeiro, Milene C Silva, Bruno A Cardoso, Leonor M Sarmento, Nádia Correia & João T Barata

  3. Immunological Cytokine Group, Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA

    Wenqing Li, Julia Tritapoe, Julie A Hixon & Scott K Durum

  4. Department of Pediatric Oncology/Hematology, Erasmus Medical Center (MC) Sophia Children's Hospital, Rotterdam, The Netherlands

    Linda Zuurbier, Rob Pieters & Jules P Meijerink

  5. Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA

    Maddalena Paganin & Adolfo A Ferrando

  6. Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain

    Maria L Toribio

  7. Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, São Paulo, Brazil

    Jörg Kobarg

  8. German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany

    Martin Horstmann

  9. The Research Institute Children's Cancer Center Hamburg, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Martin Horstmann

  10. Serviço de Hematologia/Oncologia Pediátrica, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil

    Silvia R Brandalise

  11. Department of Pathology, Columbia University Medical Center, New York, New York, USA

    Adolfo A Ferrando

  12. Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil

    J Andrés Yunes

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  1. Priscila P Zenatti
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Contributions

J.T.B. and J.A.Y. conceived and supervised the study. J.T.B., J.A.Y., S.K.D. and J.P.M. designed the experiments. J.T.B. coordinated the different contributions and wrote the paper. J.A.Y., S.K.D., J.P.M., A.A.F., W.L., D.R. and P.P.Z. contributed to the writing of portions of the paper. P.P.Z., D.R., W.L., L.Z., M.C.S., M.P., J.T., J.A.H., A.B.S., B.A.C., L.M.S. and N.C. performed experiments. J.T.B., J.A.Y., S.K.D., J.P.M., A.A.F., P.P.Z., D.R., W.L., M.C.S., A.B.S., N.C. and L.M.S. analyzed the data. M.L.T., J.K., R.P., M.H. and S.R.B. contributed reagents or clinical information.

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Correspondence to João T Barata.

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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). https://doi.org/10.1038/ng.924

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