Prognostic Significance of<i>NOTCH1</i>and<i>FBXW7</i>Mutations in Pediatric T-ALL

Erbilgin, Yücel; Sayitoğlu, Müge; Hatırnaz, Özden; Doğru, Ömer; Akçay, Arzu; Tüysüz, Gülen; Çelkan, Tiraje; Aydoğan, Gönül; Salcioglu, Zafer; Timur, Çetin; Yuksel-Soycan, Lebriz; Üre, Ümit; Anak, Sema; Ağaoğlu, Leyla; Devecioğlu, Ömer; Yıldız, İnci; Ozbek, Ugur

doi:10.1155/2010/740140

Cited by 29 publications

(38 citation statements)

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“…Thus, the primary objective of this study was to search for valid stratification criteria for patients with T-LBL. Here, we analyzed the mutational status in BLOOD, 18 APRIL 2013 x VOLUME 121, NUMBER 16 …”

Section: Discussionmentioning

confidence: 99%

“…In recent studies, activating mutations of NOTCH1 and/or FBXW7 (N/F pos ) have been observed in about 50% of pediatric patients with T-cell lymphoblastic leukemia (T-ALL; for a complete overview of publications dealing with this topic, see supplemental Table 1 on the Blood website). [9][10][11][12][13][14][15][16][17][18][19] The evolutionary highly conserved NOTCH1 signaling pathway is involved in the regulation of many cellular processes; for example, early T-cell development. 20,21 The transmembrane protein NOTCH1 is activated by the contact of NOTCH1-ligands (Delta-like 1-4, Jagged1, or Jagged2), which trigger the proteolytic cleavages releasing the protein's active part, intracellular NOTCH1 (ICN1).…”

Section: Introductionmentioning

confidence: 99%

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Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence

Bonn

Rohde

Zimmermann

et al. 2013

Blood

110

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Key Points• Confirms the prognostic effect of NOTCH1 mutations in pediatric T-cell lymphoblastic lymphoma in a large and independent cohort. • Provides the scientific basis for using NOTCH1 mutations and chromosome 6q alterations as stratification criterion in patients with T-cell lymphoblastic lymphoma.Probability of event-free survival (pEFS) in pediatric T-cell lymphoblastic lymphoma is about 80%, whereas survival in relapsed patients is very poor. No stratification criteria have been established so far. Recently, activating NOTCH1 mutations were reported to be associated with favorable prognosis, and loss of heterozygosity at chromosome 6q (LOH6q) was reported to be associated with increased relapse risk. The current project was intended to evaluate the prognostic effect of these markers. Mutations in hot spots of NOTCH1 and FBXW7 were analyzed in 116 patients. Concerning LOH6q status, 118 patients were investigated, using microsatellite marker analysis, in addition to an earlier reported cohort of 99 available patients. Ninety-two cases were evaluable for both analyses. All patients were treated with T-cell lymphoblastic lymphoma-Berlin-Frankfurt-Münster group (BFM)-type treatment. LOH6q was observed in 12% of patients (25/217) and associated with unfavorable prognosis (pEFS 27% 6 9% vs 86% 6 3%; P < .0001). In 60% (70/116) of the patients, NOTCH1 mutations were detected and associated with favorable prognosis (pEFS 84% 6 5% vs 66% 6 7%; P = .021). Interestingly, NOTCH1 mutations were rarely observed in patients with LOH in 6q16. Both prognostic markers will be used as stratification criteria in coming Non-Hodgkin Lymphoma-BFM trials. (Blood. 2013;121(16):3153-3160)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence

Bonn

Rohde

Zimmermann

et al. 2013

Blood

110

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“…The importance of correctly controlling Notch ICD half-life and the role of Fbxw7 in this process is also underscored by the fact that NOTCH1 and FBXW7 mutations can be found in T-cell acute lymphoblastic leukemia (T-ALL) (Erbilgin et al, 2010;Malyukova et al, 2007). In T-ALL patients, gain-of-function mutations in NOTCH1 are found in more than 50% of cases (Weng et al, 2004) and loss-of-function mutations in FBXW7 have also been described (Malyukova et al, 2007;Mansour et al, 2009;O'Neil et al, 2007).…”

Section: Regulation Of Notch Icd By Ubiquitylationmentioning

confidence: 99%

“…It has recently been shown that serum-and glucocorticoid-inducible kinase (SGK1) forms a trimeric complex with Notch ICD and Fbxw7, thereby enhancing Fbxw7-mediated Notch degradation (Mo et al, 2011). Functionally, Fbxw7 has been shown to be important in the control of stemness and neuronal fate versus glial differentiation in the developing brain (Matsumoto et al, 2011).The importance of correctly controlling Notch ICD half-life and the role of Fbxw7 in this process is also underscored by the fact that NOTCH1 and FBXW7 mutations can be found in T-cell acute lymphoblastic leukemia (T-ALL) (Erbilgin et al, 2010; Malyukova et al, 2007). In T-ALL patients, gain-of-function mutations in NOTCH1 are found in more than 50% of cases (Weng et al, 2004) and loss-of-function mutations in FBXW7 have also been described (Malyukova et al, 2007;Mansour et al, 2009;O'Neil et al, 2007).…”

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confidence: 99%

Notch signaling: simplicity in design, versatility in function

2011

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Notch signaling is evolutionarily conserved and operates in many cell types and at various stages during development. Notch signaling must therefore be able to generate appropriate signaling outputs in a variety of cellular contexts. This need for versatility in Notch signaling is in apparent contrast to the simple molecular design of the core pathway. Here, we review recent studies in nematodes, Drosophila and vertebrate systems that begin to shed light on how versatility in Notch signaling output is generated, how signal strength is modulated, and how cross-talk between the Notch pathway and other intracellular signaling systems, such as the Wnt, hypoxia and BMP pathways, contributes to signaling diversity.Key words: Cis-inhibition, Delta-like, Signaling diversity, Jagged, Notch, Notch intracellular domain Introduction Cells need to sense cues from their extracellular environment and integrate this information into appropriate developmental or physiological responses. Although there are a number of mechanisms that relay information from the exterior of the cell to the interior, a relatively small set of highly evolutionarily conserved signaling pathways stand out as playing particularly crucial roles in this transmission of information. In this roster of 'elite' intracellular signaling mechanisms are the Wnt pathway, the sonic hedgehog (Shh) pathway, the bone morphogenetic protein/transforming growth factor  (BMP/TGF) pathway, phosphatidylinositol 3-kinase/thymoma viral proto-oncogene (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and, the subject of this review, the Notch signaling pathway. Each of these pathways converts information about the concentration of extracellular ligands into specific transcriptional responses in the nucleus. In most cases, the signaling mechanism consists of the 'core' signaling pathway, i.e. the minimal set of protein components required for transducing the signal, and a more elaborate set of 'auxiliary' proteins, which, in various ways, impinge upon the core pathway and modify the signal but are not intrinsically necessary for relaying the signal.Among these highly conserved pathways (Gazave et al., 2009;Richards and Degnan, 2009), the Notch signaling pathway scores highly with regard to simplicity in molecular design, as it contains only a small number of core signaling components (Fig. 1). Despite this, Notch signaling affects cell differentiation decisions not only across a wide spectrum of metazoan species, but also across a broad range of cell types in a single organism and at different steps during cell lineage progression. The pleiotropic actions of Notch in different cell types and organs have recently been reviewed and are summarized in Table 1. In keeping with its important role in many cell types, the mutation of Notch genes leads to diseases in various organs and tissues (Table 2). These studies highlight the fact that the Notch pathway must be able to elicit appropriate responses in many spatially and temporally...

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“…Translocation and mutations in Notch1 may alter its function and result in overexpression and independent activation, and *60% of T-ALL cases show an increased Notch1 activity (Asnafi et al, 2009;Erbilgin et al, 2010;Koch and Radtke, 2011). The effect of Notch1 activation on the T-ALL outcome is controversial.…”

Section: The Relative Gene Expression Pattern Characteristics Of T-almentioning

confidence: 99%

The TCR γδ Repertoire and Relative Gene Expression Characteristics of T-ALL Cases with Biclonal Malignant Vδ1 and Vδ2 T Cells

Zheng

Wang²,

Ma³

et al. 2014

DNA and Cell Biology

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Prognostic Significance ofNOTCH1andFBXW7Mutations in Pediatric T-ALL

Cited by 29 publications

References 50 publications

Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence

Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence

Notch signaling: simplicity in design, versatility in function

The TCR γδ Repertoire and Relative Gene Expression Characteristics of T-ALL Cases with Biclonal Malignant Vδ1 and Vδ2 T Cells

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