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

Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, São Paulo, Brazil.
Nature Genetics (Impact Factor: 29.35). 09/2011; 43(10):932-9. DOI: 10.1038/ng.924
Source: PubMed


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.

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    • "For example, genome-wide expression profiling following JQ1 treatment identified IL7R, along with MYC, to be among the most down-regulated genes, and early studies correlated BRD4 inhibition with decreased IL7R expression and loss of BRD4 loading at the IL7R promoter across different cancer subtypes (60). Activating mutations in IL7R were recently identified in at least 9% of pediatric T-ALL, and constitutive activation of IL7R signaling in CD4−/CD8− mice thymocytes induced early T-cell precursor ALL (ETP-ALL) (61). "
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