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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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Zenatti, Priscila P. [1] ; Ribeiro, Daniel [2] ; Li, Wenqing [3] ; Zuurbier, Linda [4] ; Silva, Milene C. [2] ; Paganin, Maddalena [5] ; Tritapoe, Julia [3] ; Hixon, Julie A. [3] ; Silveira, Andre B. [1] ; Cardoso, Bruno A. [2] ; Sarmento, Leonor M. [2] ; Correia, Nadia [2] ; Toribio, Maria L. [6] ; Kobarg, Joerg [7] ; Horstmann, Martin [8, 9] ; Pieters, Rob ; Brandalise, Silvia R. [1, 10] ; Ferrando, Adolfo A. [5, 11] ; Meijerink, Jules P. [4] ; Durum, Scott K. [3] ; Yunes, J. Andres [1, 12] ; Barata, Joao T. [2]
Total Authors: 22
Affiliation:
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[1] Ctr Infantil Boldrini, Lab Biol Mol, Campinas, SP - Brazil
[2] Univ Lisbon, Fac Med, Inst Med Mol, Canc Biol Unit, P-1699 Lisbon - Portugal
[3] NCI, Immunol Cytokine Grp, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21701 - USA
[4] Erasmus Med Ctr MC Sophia Childrens Hosp, Dept Pediat Oncol Hematol, Rotterdam - Netherlands
[5] Columbia Univ Med Ctr, Inst Canc Genet, New York, NY - USA
[6] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, CSIC, Madrid - Spain
[7] CNPEM, LNBio, Campinas, SP - Brazil
[8] German Cooperat Study Grp Childhood Acute Lymphob, Hamburg - Germany
[9] Univ Med Ctr Hamburg Eppendorf, Clin Pediat Hematol & Oncol, Childrens Canc Ctr Hamburg, Res Inst, Hamburg - Germany
[10] Univ Estadual Campinas, Serv Hematol Oncol Pediat, Campinas, SP - Brazil
[11] Columbia Univ Med Ctr, Dept Pathol, New York, NY - USA
[12] Univ Estadual Campinas, Fac Ciencias Med, Dept Genet Med, Campinas, SP - Brazil
Total Affiliations: 12
Document type: Journal article
Source: Nature Genetics; v. 43, n. 10, p. 932-U31, OCT 2011.
Web of Science Citations: 186
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. (AU)

FAPESP's process: 08/10034-1 - Bone marrow microenvironment and PI3K pathway in resistance to chemotherapy of pediatric acute lymphoblastic leukemia
Grantee:José Andrés Yunes
Support type: Regular Research Grants