NOTCH mutations as prognostic markers in T-ALL

Ferrando, Adolfo A.

doi:10.1038/leu.2010.237

Cited by 29 publications

(25 citation statements)

References 13 publications

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“…Interestingly, NOTCH1 mutations have been found to be an adverse prognostic marker in CLL 30,31 but not in T-ALL where they are associated with improved response to primary treatment and inconsistently with improved survival. 45 The sensitivity of the Rec-1 and the SP-49 cell lines to compound E suggests that NOTCH1 mutations could serve as a target for tailored therapy in a subset of MCLs. However, the study of ␥-secretase inhibitors that function as pan-NOTCH inhibitors has so far been hampered by low clinical activity and mainly gastrointestinal toxicity.…”

Section: Discussionmentioning

confidence: 99%

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Kridel

Meissner

Rogić

et al. 2012

Blood

304

254

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Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P ‫؍‬ .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.

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Section: Discussionmentioning

confidence: 99%

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Kridel

Meissner

Rogić

et al. 2012

Blood

304

254

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“…35 advances in the molecular typing of leukemia, many new genetic alterations, including mutations and deletions, have been identified. However, their prognostic values have not been widely verified and the results may be controversial [24][25][26][27][28][29][30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

Yang

Hsiao

Chen

et al. 2011

Pediatric Blood & Cancer

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BackgroundThe absence of biallelic TCRγ deletion (ABD) is a characteristic of early thymocyte precursors before V(D)J recombination. The ABD was reported to predict early treatment failure in T‐cell acute lymphoblastic leukemia (ALL). This study aimed to investigate its prognostic value in Taiwanese patients with T‐cell ALL.ProcedureForty‐five children with T‐cell ALL were enrolled from six medical centers in Taiwan. Quantitative DNA polymerase chain reaction (Q‐PCR) was performed to check the status of TCRγ deletion. The threshold for homozygous deletions by Q‐PCR was defined as a fold‐change <0.35.ResultsABD was found in 20 patients [20:45] who had higher incidences of induction failure than those without ABD (P = 0.03; hazard ratio [HR] = 8.13; 95% confidence interval [95% CI] = 1.23–53.77) after multivariate regression analysis. Patents with ABD also had inferior EFS and OS (P = 0.071 and 0.0196, respectively). Multivariate Cox analysis indicated that the association between ABD and overall survival was independent of age and leukocyte count on presentation (P = 0.036; HR = 4.25; 95% CI = 1.10–16.42).ConclusionsThe absence of TCRγ deletion is a predictor of a poor response to induction chemotherapy for pediatric patients with T‐cell ALL in Taiwan. Providing patients with T‐cell ALL and ABD with alternative regimens may be worthwhile to test in future clinical trials. Pediatr Blood Cancer 2012; 58: 846–851. © 2011 Wiley Periodicals, Inc.

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“…Furthermore, activated NOTCH1 protein expression was more frequently detected in malignant ACTs. However, no activating mutations in the PEST region of the NOTCH1 gene (Weng et al 2004, Jundt et al 2008, Ferrando 2010, Fabbri et al 2011, Paganin & Ferrando 2011, Rossi et al 2012 were detected in ACCs. Of note, although gene expression of Notch1 pathway components correlated significantly in normal adrenals and adenomas, this relationship was lost in ACCs, which indicates dysregulation of Notch1 signaling in malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the translocation t(7;9)(q34;q34.3) or mutations in the NOTCH gene (including PEST truncating mutations), which lead to Notch-ligand independent activation or to impaired degradation of activated Notch, have been shown to play a role in T-cell acute lymphoblastic leukemia (Weng et al 2004, Jundt et al 2008, Ferrando 2010, Paganin & Ferrando 2011. In solid tumors, both oncogenic actions or a tumor suppressor role of the Notch signaling pathway and its components have been reported, depending on the cell type and context (Supplementary Table S1, see section on supplementary data given at the end of this article) (Radtke & Raj 2003, Balint et al 2005, Wang et al 2006, Westhoff et al 2009, Lobry et al 2011, Mazur et al 2012, Rizzo et al 2013, Carvalho et al 2014, Du et al 2014.…”

Section: Introductionmentioning

confidence: 99%

Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome

Ronchi¹,

Sbiera²,

Altieri³

et al. 2015

Endocrine-Related Cancer

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Previous SNP array analyses have revealed genomic alterations of the Notch pathway as being the most frequent abnormality in adrenocortical tumors (ACTs). The aim of the present study was to evaluate the expression of components of Notch signaling in ACTs and to correlate them with clinical outcome. The mRNA expression of JAG1, NOTCH1, and selected target genes of NOTCH1 (HES1, HES5, and HEY2) was evaluated in 80 fresh frozen samples (28 normal adrenal glands (NAGs), 24 adenomas (ACAs), and 28 carcinomas (ACCs)) by quantitative RT-PCR. Immunohistochemistry was performed in 221 tissues on paraffin slides (16 NAGs, 27 ACAs, and 178 ACCs) for JAG1, activated NOTCH1 (aNOTCH1), and HEY2. An independent ACC validation cohort (nZ77) was then also investigated. HEY2 mRNA expression was higher in ACCs than it was in ACAs (P!0.05). The protein expression of all of the factors was high (H-score 2-3) in a larger proportion of ACCs as compared to ACAs and NAGs (JAG1 in 27, 15, and 10%; aNOTCH1 in 13, 8, and 0%; HEY2 in 66, 61, and 33% respectively, all P!0.001). High JAG1 expression was associated with earlier tumor stages and lower numbers of metastases in ACCs (both PZ0.08) and favorably impacted overall and progression-free survival (PFS) (131 vs 30 months, hazard ratio (HR) 0.45, and 37 vs 9 months, HR 0.51, both P!0.005). This impact on overall survival (OS) was confirmed in the validation cohort. No such association was observed for aNOTCH1 or HEY2. In conclusion, different components of the Notch1 signaling pathway are overexpressed in ACCs, which suggests a role for the pathway in malignant transformation. However, JAG1 is overexpressed in a subgroup of ACCs with a better clinical outcome.

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NOTCH mutations as prognostic markers in T-ALL

Cited by 29 publications

References 13 publications

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome

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