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

  1. Author:
    Zenatti, P. P.
    Ribeiro, D.
    Li, W. Q.
    Zuurbier, L.
    Silva, M. C.
    Paganin, M.
    Tritapoe, J.
    Hixon, J. A.
    Silveira, A. B.
    Cardoso, B. A.
    Sarmento, L. M.
    Correia, N.
    Toribio, M. L.
    Kobarg, J.
    Horstmann, M.
    Pieters, R.
    Brandalise, S. R.
    Ferrando, A. A.
    Meijerink, J. P.
    Durum, S. K.
    Yunes, J. A.
    Barata, J. T.

  2. Author Address

    [Ribeiro, D; Silva, MC; Cardoso, BA; Sarmento, LM; Correia, N; Barata, JT] Univ Lisbon, Fac Med, Inst Med Mol, Canc Biol Unit, P-1699 Lisbon, Portugal. [Zenatti, PP; Silveira, AB; Brandalise, SR; Yunes, JA] Ctr Infantil Boldrini, Lab Biol Mol, Campinas, SP, Brazil. [Li, WQ; Tritapoe, J; Hixon, JA; Durum, SK] NCI, Immunol Cytokine Grp, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Zuurbier, L; Meijerink, JP] Erasmus Med Ctr MC Sophia Childrens Hosp, Dept Pediat Oncol Hematol, Rotterdam, Netherlands. [Paganin, M; Ferrando, AA] Columbia Univ Med Ctr, Inst Canc Genet, New York, NY USA. [Toribio, ML] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, CSIC, Madrid, Spain. [Kobarg, J] CNPEM, LNBio, Campinas, SP, Brazil. [Horstmann, M] German Cooperat Study Grp Childhood Acute Lymphob, Hamburg, Germany. [Horstmann, M] Univ Med Ctr Hamburg Eppendorf, Clin Pediat Hematol & Oncol, Childrens Canc Ctr Hamburg, Res Inst, Hamburg, Germany. [Brandalise, SR] Univ Estadual Campinas, Serv Hematol Oncol Pediat, Campinas, SP, Brazil. [Ferrando, AA] Columbia Univ Med Ctr, Dept Pathol, New York, NY USA. [Yunes, JA] Univ Estadual Campinas, Fac Ciencias Med, Dept Genet Med, Campinas, SP, Brazil.;Barata, JT (reprint author), Univ Lisbon, Fac Med, Inst Med Mol, Canc Biol Unit, P-1699 Lisbon, Portugal;joao_barata@fm.ul.pt
    1. Year: 2011
    2. Date: Oct
  2. Journal: Nature Genetics
    1. 43
    2. 10
    3. Pages: 932-U31
  4. Type of Article: Article
  5. ISSN: 1061-4036
  1. 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.

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External Sources

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  2. DOI: 10.1038/ng.924
  3. View record in Web of Science®
  4. WOS: 000295316200006

Library Notes

  1. Fiscal Year: FY2011-2012
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