Dataset Information

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

ABSTRACT: Interleukin 7 (IL-7) and its receptor, formed by IL-7R? (encoded by IL7R) and ?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-7R? subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, ?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.

SUBMITTER: Zenatti PP

PROVIDER: S-EPMC7424552 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Zenatti Priscila P PP Ribeiro Daniel D Li Wenqing W Zuurbier Linda L Silva Milene C MC Paganin Maddalena M Tritapoe Julia J Hixon Julie A JA Silveira André B AB Cardoso Bruno A BA Sarmento Leonor M LM Correia Nádia N Toribio Maria L ML Kobarg Jörg J Horstmann Martin M Pieters Rob R Brandalise Silvia R SR Ferrando Adolfo A AA Meijerink Jules P JP Durum Scott K SK Yunes J Andrés JA Barata João T JT

Nature genetics 20110904 10

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 intermolecul ...[more]

PMID: 21892159

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Project description:Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent genetic aberrations. The identification of those abnormalities is clinically important because they are considered significant risk-stratifying markers.There are insufficient data of cytogenetic profiles in Saudi Arabian patients with childhood ALL leukemia. We have examined a cohort of 110 cases of ALL to determine the cytogenetic profiles and prevalence of FLT3 mutations and analysis of the more frequently observed abnormalities and its correlations to other biologic factors and patient outcomes and to compare our results with previously published results.Patients-We reviewed all cases from 2007 to 2016 with an established diagnosis of childhood ALL. Of the 110 patients, 98 were B-lineage ALL and 12 T-cell ALL. All the patients were treated by UKALL 2003 protocol and risk stratified according previously published criteria. Cytogenetic analysis-Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Analysis of FLT3 mutations-Bone marrow or blood samples were screened for FLT3 mutations (internal tandem duplications, and point mutations, D835) using polymerase chain reaction methods.Cytogenetic analysis showed chromosomal anomalies in 68 out of 102 cases with an overall incidence 66.7%. The most frequent chromosomal anomalies in ALL were hyperdiploidy, t(9;22), t(12;21), and MLL gene rearrangements. Our data are in accordance with those published previously and showed that FLT3 mutations are not common in patients with ALL (4.7%) and have no prognostic relevance in pediatric patients with ALL. On the contrary, t(9;22), MLL gene rearrangements and hypodiploidy were signs of a bad prognosis in childhood ALL with high rate of relapse and shorter overall survival compared with the standard-risk group (P = .031).The event-free survival was also found to be worse (P = .040).Our data are in accordance with those published previously, confirming the overall frequency of cytogenetic abnormalities and their prognostic relevance.

Dataset Information

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

Publications

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

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