title: Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia.
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.
authors: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, São Paulo, Brazil.
authors: Priscila P
authors: PP
authors: Zenatti
authors: Daniel
authors: D
authors: Ribeiro
authors: Wenqing
authors: W
authors: Li
authors: Linda
authors: L
authors: Zuurbier
authors: Milene C
authors: MC
authors: Silva
authors: Maddalena
authors: M
authors: Paganin
authors: Julia
authors: J
authors: Tritapoe
authors: Julie A
authors: JA
authors: Hixon
authors: André B
authors: AB
authors: Silveira
authors: Bruno A
authors: BA
authors: Cardoso
authors: Leonor M
authors: LM
authors: Sarmento
authors: Nádia
authors: N
authors: Correia
authors: Maria L
authors: ML
authors: Toribio
authors: Jörg
authors: J
authors: Kobarg
authors: Martin
authors: M
authors: Horstmann
authors: Rob
authors: R
authors: Pieters
authors: Silvia R
authors: SR
authors: Brandalise
authors: Adolfo A
authors: AA
authors: Ferrando
authors: Jules P
authors: JP
authors: Meijerink
authors: Scott K
authors: SK
authors: Durum
authors: J Andrés
authors: JA
authors: Yunes
authors: João T
authors: JT
authors: Barata
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D002470:Cell Survival; D002648:Child; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009857:Oncogenes; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018398:Homeodomain Proteins; D015851:Interleukin-7; D034741:RNA, Small Interfering; D020395:Receptors, Interleukin-7; C489494:TLX3 protein, human; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D003545:Cysteine