Article

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: 29.65). 09/2011; 43(10):932-9. DOI: 10.1038/ng.924
Source: PubMed

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.

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    • "the RAS signaling pathway [Balgobind et al. 2008; Bar-Eli et al. 1989; Campbell and Der, 2004], activating mutations in JAK1 and JAK3 [Flex et al. 2008; Zhang et al. 2012], activating mutations in IL7R [Zenatti et al. 2011; Zhang et al. 2012], FLT3 mutations [Paietta et al. 2004], PTPN2 deletions [Kleppe et al. 2011] and IRS4 translocations [Karrman et al. 2009]. Finally, deletions and loss of function mutations in histone-modifying genes such as SUZ12, EED, EZH2, and SETD2 have been found in T-ALL, which highlight the role of altered epigenetic regulation in T-cell transformation [Ntziachristos et al. 2012; Zhang et al. 2012]. "
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    • "Using the mRNA-seq mutant allele read counts, we estimated the IL7R mutation to be expressed in approximately 93.4% of cells in the sample sequenced. Similar activating mutations in IL7R have recently been described in pediatric B and T-lineage ALL (Shochat et al., 2011; Zenatti et al., 2011; Zhang et al., 2012). Interestingly, case PALJDL also harbored a focal homozygous deletion removing the first two exons of SH2B3 that was not evident by SNP array analysis, with a concomitant absence of SH2B3 expression by mRNA-seq analysis (Figures 5B and 5C). "
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    • ", and FBXW7 were sequenced. Primer sequences used for FLT3 (Van Vlierberghe et al., 2005), DNMT3A (Ley et al., 2010), IDH1 (Andersson et al., 2011), IDH2 (Andersson et al., 2011), NOTCH1 (Weng et al., 2004), IL7R (Zenatti et al., 2011), and FBXW7 (Thompson et al., 2007) have been previously described. Primer sequences used for ETV6 sequencing are shown in Table S4. "
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