Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness

Messina, Monica; Giudice, Ilaria Del; Khiabanian, Hossein; Rossi, Davide; Chiaretti, Sabina; Rasi, Silvia; Spina, Valeria; Holmes, Antony B.; Marinelli, M; Fabbri, Giulia; Piciocchi, Alfonso; Mauro, Francesca Romana; Guarini, Anna; Gaïdano, Gianluca; Dalla‐Favera, Riccardo; Pasqualucci, Laura; Rabadán, Raúl; Foà, Robin

doi:10.1182/blood-2013-10-534271

Cited by 78 publications

(61 citation statements)

References 58 publications

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“…9,28 All mutations found within RPS15 were missense SNVs (n 5 7) or multiple nucleotide variants (n 5 1) and, with the exception of 1 SNV, clustered to a 7 amino-acid evolutionarily conserved region within exon 4 ( Figure 2A; supplemental Figure 1). Of note, 3 RPS15-wt cases carried mutations within 2 other ribosomal genes (ie, RPSA and RPS20) (supplemental Table 7).…”

Section: Resultsmentioning

confidence: 99%

“…Such mutations tend to be enriched in high-risk CLL patients and have been associated with inferior outcome and even chemo-refractory disease. [4][5][6][7][8][9][10][11][12][13] New technologies have also facilitated the exploration into the clonal architecture of CLL, not only at a single time point, but also throughout the disease course, by analyzing longitudinal samples. 14,15 From these pioneering studies, it became evident that subclonal mutations (ie, variants detected in only a fraction of the tumor population) could be present at low frequencies, even remaining undetected, at early stages of the disease; however, they can be positively selected as the disease progresses, particularly after several lines of therapy.…”

Section: Introductionmentioning

confidence: 99%

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Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

Ljungström

Cortese

Young

et al. 2016

Blood

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Key Points• Whole-exome sequencing of CLL patients who relapsed after FCR treatment revealed frequent mutations in RPS15.• RPS15 mutations are likely to be early clonal events and confer poor prognosis.Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

Ljungström

Cortese

Young

et al. 2016

Blood

Self Cite

132

140

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“…15 In the present cohort of refractory/relapsed cases we identified a high number of lesions, strengthening the previous observation that the genetic complexity is correlated with an increased likelihood of drug resistance. 9,27,28 Besides SET-NUP214 fusions, out-of-frame fusions resulting in deregulated expression or in inactivation of transcriptional regulators or tumor suppressor genes were detected, including four TCR fusions. A novel rearrangement joining TRAC to SOX8 on 16p13 was identified.…”

Section: Discussionmentioning

confidence: 99%

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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“…Probes targeting all coding exons or hotspot regions of 27 known CLL driver genes and/or genes previously reported in EGR2-mutated CLL 19,29,[37][38][39][40][41][42][43][44] were designed using Agilent"s SureDesign service (https://earray.chem.agilent.com/suredesign/home.htm, Supplemental Table S4). …”

Section: Analysis Of Concurrent Mutations By Targeted Deep-sequencingmentioning

confidence: 99%

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

et al. 2016

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EGR2 mutations in CLL 5 AbstractRecurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%), and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

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Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness

Cited by 78 publications

References 58 publications

Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

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

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

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