Analysis of the chronic lymphocytic leukemia coding genome: role of <i>NOTCH1</i> mutational activation

Fabbri, Giulia; Rasi, Silvia; Rossi, Davide; Трифонов, Владимир; Khiabanian, Hossein; Ma, Jing; Grunn, Adina; Fangazio, Marco; Capello, Daniela; Monti, Sara; Cresta, Stefania; Gargiulo, Ernesto; Forconi, Francesco; Guarini, Anna; Arcaini, Luca; Paulli, Marco; Laurenti, Luca; Larocca, Luigi Maria; Marasca, Roberto; Gattei, Valter; Oscier, David; Bertoni, Francesco; Mullighan, Charles G.; Foà, Robin; Pasqualucci, Laura; Rabadán, Raúl; Dalla‐Favera, Riccardo; Gaïdano, Gianluca

doi:10.1084/jem.20110921

Cited by 571 publications

(693 citation statements)

References 66 publications

Supporting

Mentioning

634

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Progressive disease is characterised by unmutated immunoglobulin heavy variable (IGHV) genes, ZAP70 and CD38 expression. 1 Genetic markers including deletions of 17p, 11q and 13q, trisomy 12 and TP53 mutations [2][3][4] have been known to impact prognosis for some time, however with the emergence of next generation sequencing, a plethora of new genetic alterations have been identified including NOTCH1 (10-15%) [5][6][7][8] and SF3B1 (10-17%) [8][9][10] mutations which identify patients with progressive disease. 8 SF3B1 is one of the proteins that make up the spliceosome and regulates excision of introns from premRNA 11 .…”

Section: Introductionmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

View full text Add to dashboard Cite

The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

show abstract

“…Second, our actuarial analysis indicates that NOTCH1-mutated patients display a higher risk of developing RS, a condition that is frequently lethal and recurrently harbors NOTCH1 mutations that, importantly, are present already at the time of CLL presentation in a significant fraction of RS patients. 19 A potential association of NOTCH1 mutations with chemorefractoriness may further explain the poor outcome associated with NOTCH1 alterations. Although the relationship between NOTCH1 mutations and response to treatment needs to be formally tested within clinical trials, indirect evidence for this hypothesis comes from the observation that NOTCH1 mutations are enriched among chemorefractory CLL patients, 19,20 and that NOTCH1 activation in vitro confers resistance to apoptosis through nuclear factor-kB pathway activation.…”

Section: Mutations Of Notch1 In High-risk Cllmentioning

confidence: 99%

“…19,20 Removal of the PEST domain results in NOTCH1-impaired degradation and accumulation of an active NOTCH1 isoform sustaining deregulated signaling. A practically important feature of the NOTCH1 mutational spectrum is that one single recurrent mutation (c.7544_7545delCT) accounts for B80% of all NOTCH1 mutations detectable in CLL.…”

Section: Mutations Of Notch1 In High-risk Cllmentioning

confidence: 99%

“…19,21 A potential association of NOTCH1 mutations with chemorefractoriness may further explain the poor outcome associated with NOTCH1 alterations. Although the relationship between NOTCH1 mutations and response to treatment needs to be formally tested in clinical trials, indirect evidence for this hypothesis comes from the observation that NOTCH1 mutations are enriched among chemorefractory CLL patients, and that NOTCH1 activation in vitro confers resistance to apoptosis through nuclear factor-kB pathway activation.…”

Section: Perspectivesmentioning

confidence: 99%

See 1 more Smart Citation

The genome of chemorefractory chronic lymphocytic leukemia reveals frequent mutations of NOTCH1 and SF3B1

et al. 2012

View full text Add to dashboard Cite

Next-generation whole-exome sequencing has revealed two novel genes, namely NOTCH1 and SF3B1, whose mutations predict poor outcome and preferentially associate with chemorefractory chronic lymphocytic leukemia (CLL). Analysis of 539 CLL cases documents that NOTCH1 mutations i) represent one of the most frequent cancer gene mutations involved at presentation; ii) cluster with cases harboring trisomy 12 and tend to be mutually exclusive with TP53 disruption among genetic subgroups; iii) identify high-risk patients showing poor survival similar to that associated with TP53 abnormalities; and iv) exert a prognostic role independent of widely accepted clinical and genetic risk factors. Mutations of SF3B1, a splicing factor that is a critical component of the spliceosome, recurrently associate with fludarabine-refractory CLL, occur at a low rate at CLL presentation and have a minor role in Richter transformation, corroborating the notion that CLL histological shift is molecularly distinct from chemorefractory progression without the Richter transformation.Leukemia Supplements (2012) 1, S26--S28; doi:10.1038/leusup.2012.16Keywords: chronic lymphocytic leukemia; prognostic markers; pathogenesis; NOTCH1; SF3B1; mutations Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. 1--3 The clinical course of CLL ranges from very indolent, with a nearly normal life expectancy, 1--3 to rapidly progressive, leading to death, and occasionally undergoing transformation to aggressive lymphoma, known as Richter syndrome (RS). 1--5 At presentation, several clinical and biological features may help predict, at least in part, the clinical course of CLL. 6--8 Of the biological prognosticators that have been developed, current guidelines for clinical practice recommend screening only for TP53 disruption by mutation and/or deletion of the locus, which identifies a fraction of high-risk CLL patients destined to experience a very short survival. 8--15 High-risk CLL, however, cannot be fully recapitulated by TP53 disruption, as 40--50% high-risk CLL patients are devoid of TP53 abnormalities. 16 Thus, it is conceivable that other genetic lesions may drive CLL aggressiveness and/or may cause the chemorefractory phenotype of the disease.Genome-wide methods, including whole-exome sequencing (WES), allow the characterization of the entire spectrum of mutations present in a given disease, as documented by the example of other B-cell malignancies. 17,18 On these grounds, investigating the CLL genome may be useful to provide further insights into CLL pathogenesis, and might contribute to elucidate the molecular basis of CLL clinical evolution, including RS transformation and development of chemorefractoriness. We have exploited an integrated approach based on next-generation WES to investigate the CLL-coding genome. This approach has revealed two novel genes, namely NOTCH1 and SF3B1, whose mutations predict poor outcome and preferentially associate with chemorefractory CLLs. 19--21 MUTATIONS OF NOTCH1 IN HIGH-RISK CLLWe ha...

show abstract

Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation

Abstract: Next generation sequencing and copy number analysis provide insights into the complexity of the CLL coding genome, and reveal an association between NOTCH1 mutational activation and poor prognosis.

Cited by 571 publications

References 66 publications

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

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

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

The genome of chemorefractory chronic lymphocytic leukemia reveals frequent mutations of NOTCH1 and SF3B1

Contact Info

Product

Resources

About