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

• Published in: Nature genetics Vol. 43; no. 10; pp. 932 - 939
• Main Authors: Barata, João T, Zenatti, Priscila P, Ribeiro, Daniel, Li, Wenqing, Zuurbier, Linda, Silva, Milene C, Paganin, Maddalena, Tritapoe, Julia, Hixon, Julie A, Silveira, André B, Cardoso, Bruno A, Sarmento, Leonor M, Correia, Nádia, Toribio, Maria L, Kobarg, Jörg, Horstmann, Martin, Pieters, Rob, Brandalise, Silvia R, Ferrando, Adolfo A, Meijerink, Jules P, Durum, Scott K, Yunes, J Andrés
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2011; Nature Publishing Group
• Subjects: 631/208/737; 692/420/755; 692/699/67/1990/291/1621/1916; Acute lymphocytic leukemia; Agriculture; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Cycle; Cell Line; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Child; Cysteine - genetics; Cysteine - metabolism; DNA Mutational Analysis; Exons; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene Function; Gene mutations; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Hematologic and hematopoietic diseases; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Human Genetics; Humans; Interleukin-7 - genetics; Interleukin-7 - metabolism; Interleukins; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Janus Kinase 3 - genetics; Janus Kinase 3 - metabolism; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Knockout; Molecular and cellular biology; Mutation; Oncogenes; Pediatrics; Physiological aspects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Proteins; Receptors, Interleukin-7 - genetics; Receptors, Interleukin-7 - metabolism; Regression analysis; Risk factors; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Sequence Analysis, DNA; Signal Transduction; T-Lymphocytes - metabolism; Transfection; Tumor Cells, Cultured; United States; Lymphoproliferative syndrome; T-Lymphocyte; Acute leukemia; Malignant hemopathy; Mutation; Acute lymphocytic leukemia; Carcinogenesis; Cancer
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.924

João Barata and colleagues identify somatic gain-of-function IL7R mutations in childhood T-cell acute lymphoblastic leukemia. The mutations result in constitutive receptor activation, implicating the IL-7R pathway as a potential therapeutic target in a subset of T-ALL cases. 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.