The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse

Bandapalli, Obul Reddy; Schuessele, Stephanie; Kunz, Joachim; Rausch, Tobias; Stütz, Adrian M.; Tal, Noa; Geron, Ifat; Gershman, Nava; Izraeli, Shai; Eilers, Juliane; Vaezipour, Nina; Kirschner-Schwabe, Renate; Hof, Jana; Stackelberg, Arend von; Schrappe, Martin; Stanulla, Martin; Zimmermann, Martin; Koehler, Rolf; Avigad, Smadar; Handgretinger, Rupert; Frismantas, Viktoras; Bourquin, Jean‐Pierre; Bornhäuser, Beat; Korbel, Jan; Muckenthaler, Martina U.; Kulozik, Andreas E.

doi:10.3324/haematol.2014.104992

Cited by 104 publications

(104 citation statements)

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“…This mutation has been reported to be also the most frequent mutation in T-ALL and HSTCL (Bandapalli et al, 2014;Nicolae et al, 2014). All mutations described in our study affecting STAT5B were located in the SH2 domain and most probably increase transcriptional activity and phosphorylation of the mutant protein (Bandapalli et al, 2014;Nicolae et al, 2014).…”

Section: Discussionmentioning

confidence: 77%

Genes encoding members of the JAK‐STAT pathway or epigenetic regulators are recurrently mutated in T‐cell prolymphocytic leukaemia

et al. 2016

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T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia. The primary genetic alteration in T-PLL are the inv(14)(q11q32)/t(14;14)(q11;q32) leading to TRD/TRA-TCL1A fusion, or the t(X;14)(q28;q11) associated with TRD/TRA-MTCP1 fusion. However, additional cooperating abnormalities are necessary for emergence of the full neoplastic phenotype. Though the pattern of secondary chromosomal aberrations is remarkably conserved, targets of the changes are largely unknown. We analysed a cohort of 43 well-characterized T-PLL for hotspot mutations in the genes JAK3, STAT5B and RHOA. Additionally, we selected a subset of 23 T-PLL cases for mutational screening of 54 genes known to be recurrently mutated in T-cell and other haematological neoplasms. Activating mutations in the investigated regions of the JAK3 and STAT5B genes were detected in 30% (13/43) and 21% (8/39) of the cases, respectively, and were mutually exclusive. Further, we identified mutations in the genes encoding the epigenetic regulators EZH2 in 13% (3/23), TET2 in 17% (4/23) and BCOR in 9% (2/23) of the cases. We confirmed that the JAK-STAT pathway is a major mutational target, and identified epigenetic regulators recurrently mutated in T-PLL. These findings complement the mutational spectrum of secondary aberrations in T-PLL and underscore the potential therapeutical relevance of epigenetic regulators in T-PLL.

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Section: Discussionmentioning

confidence: 77%

Genes encoding members of the JAK‐STAT pathway or epigenetic regulators are recurrently mutated in T‐cell prolymphocytic leukaemia

et al. 2016

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“…36 Conversely, Bandapalli et al identified a high rate of STAT5B mutations in relapsed pediatric patients. 44 In the present study, RNAseq analysis revealed a high incidence of mutations in the JAK/STAT pathway in refractory/relapsed cases, indicating that these lesions are a hallmark of very poor prognosis in T-ALL. The majority of mutations detected involve JAK3, in line with the observation that JAK3 mutations are drivers of T-ALL.…”

Section: A B Cmentioning

confidence: 95%

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

et al. 2016

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Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.

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“…12,15,18,31 However, the exact frequency of mutations for all members of the signaling pathway is unclear. In our series, sequence mutations/copy number variations of the IL7R, JAK1, JAK3 and STAT5 genes were found in 27.7% of cases, confirming that this signaling pathway is an important oncogenic axis in T-ALL ( Figure 4A).…”

Section: A B Cmentioning

confidence: 99%

Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

et al. 2015

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JAK signaling pathway members in 27.7% of T-ALL samples screened; an observation with therapeutic potential. Statistically significant pairwise associations were found between different mutations, indicating the presence of functional interactions among different pathways in T-ALL pathogenesis. Of significance, we found a mutually exclusive relationship between IL7R-JAK mutations and the presence of TAL1/LMO2 rearrangements. We also identified positive correlations among IL7R-JAK mutations and mutations/deletions in PHF6 and members of the PRC2 complex. Our findings begin to unravel the diversity of genetic lesions that are implicated in the development of T-ALL. Methods DNA samplesT-ALL samples from patients (n=155: 111 children, 44 adults) were collected from various institutions (Online Supplementary Table S1). The diagnosis of T-ALL was based on morphology, cytochemistry and immunophenotyping according to World Health Organization criteria. Genomic DNA was isolated from bone marrow (either fixed or fresh bone marrow cells). 5,21,22 To investigate the prognostic relevance of IL7R, JAK1 and JAK3 mutations, Sanger sequencing was used to screen for mutations in these three genes in an independent cohort of 78 T-ALL patients. Those patients were all enrolled into the United Kingdom (UK) Children's Cancer and Leukaemia Group (CCLG) ALL2003 trial. 23This study was approved by the ethics committees of the institutes involved and informed consent was obtained from the participants. Samples and clinical data were stored in accordance with the declaration of Helsinki. Capture designSureDesign software was used to design two slightly different Haloplex capture assays (Table 1). The total amplicon number for design A was 23,127 with a region size of 472.006 kbp and a predicted target coverage of >99%. For design B the total amplicon number was 19,694 with a region size of 418.373 kbp and a predicted target coverage of >99%. For this study, 80 samples were processed with design A and 75 samples with design B. In both assays, the coding exons of selected genes (based on RefSeq, CCDS and VEGA databases) were targeted with an extra ten bases upstream and downstream. Targeted regions comprised the coding sequence of genes that were either recently identified as recurrently mutated in ALL or other hematologic malignancies (known driver genes) or were similar to known oncogenes (candidate driver genes) to be sequenced. 18,19,24,25 For statistical analyses we only considered the 115 genes that were sequenced in both Haloplex designs (Online Supplementary Table S2). Library preparation and sequencing were performed as described in the Online Supplementary Material. Data analysesIn NextGENe software (v2.2.1, Softgenetics, State College, PA, USA), we performed the following steps: (i) the fastQ output file was converted into a FASTA file to eliminate reads that were not "paired" and that did not meet the criteria of the default settings; (ii) reads from the converted unique FASTA file were aligned to the reference genome (...

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The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse

Cited by 104 publications

References 15 publications

Genes encoding members of the JAK‐STAT pathway or epigenetic regulators are recurrently mutated in T‐cell prolymphocytic leukaemia

Genes encoding members of the JAK‐STAT pathway or epigenetic regulators are recurrently mutated in T‐cell prolymphocytic leukaemia

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

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