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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Available from: Nádia Correia, Aug 20, 2015
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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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    ABSTRACT: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of activating NOTCH1 mutations highlights the critical role of NOTCH signaling in the pathogenesis of this disease and has prompted the development of therapeutic approaches targeting the NOTCH signaling pathway. Small molecule gamma secretase inhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical testing for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are strongly synergistic and may overcome the gastrointestinal toxicity associated with systemic inhibition of the NOTCH pathway. In addition, emerging new anti-NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 antibodies and stapled peptides targeting the NOTCH transcriptional complex in the nucleus.
    06/2013; 4(3):199-210. DOI:10.1177/2040620712471368
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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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    ABSTRACT: Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2, and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2-negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.
    Cancer cell 08/2012; 22(2):153-66. DOI:10.1016/j.ccr.2012.06.005 · 23.89 Impact Factor
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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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    ABSTRACT: Early immature T cell acute lymphoblastic leukemias (T-ALLs) account for ~5-10% of pediatric T-ALLs and are associated with poor prognosis. However, the genetic defects that drive the biology of these tumors remain largely unknown. In this study, analysis of microarray gene expression signatures in adult T-ALL demonstrated a high prevalence of early immature leukemias and revealed a close relationship between these tumors and myeloid leukemias. Many adult immature T-ALLs harbored mutations in myeloid-specific oncogenes and tumor suppressors including IDH1, IDH2, DNMT3A, FLT3, and NRAS. Moreover, we identified ETV6 mutations as a novel genetic lesion uniquely present in immature adult T-ALL. Our results demonstrate that early immature adult T-ALL represents a heterogeneous category of leukemias characterized by the presence of overlapping myeloid and T-ALL characteristics, and highlight the potential role of ETV6 mutations in these tumors.
    Journal of Experimental Medicine 12/2011; 208(13):2571-9. DOI:10.1084/jem.20112239 · 13.91 Impact Factor
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