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

Author(s):Show less -

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]

Affiliation:Show less -

^[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

• 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