Prognostic significance of NOTCH1 and FBXW7 mutations in pediatric T-ALL

Institute of Experimental Medicine, Department of Genetics, Istanbul University, Istanbul, Turkey.
Disease markers (Impact Factor: 1.56). 08/2010; 28(6):353-60. DOI: 10.3233/DMA-2010-0715
Source: PubMed


The NOTCH signaling pathway plays important role in the development of multicellular organisms, as it regulates cell proliferation, survival, and differentiation. In adults, it is essential for the T- or B-lymphocyte lineage commitment. NOTCH1 and FBXW7 mutations both lead the activation of the NOTCH1 pathway and are found in the majority of T-ALL patients. In this study, the mutation analysis of NOTCH1 and FBXW7 genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols. In 19 patients (22%), activating NOTCH1 mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases (10%) demonstrated FBXW7 mutations (2 cases had both NOTCH1 and FBXW7 mutations). We also analyzed the relationship of the mutation data between the clinical and biological data of the patients. NOTCH1 and FBXW7, NOTCH1 alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype. However, NOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs.

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Available from: Ozden Hatirnaz, Feb 07, 2014
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    • "Acquired NOTCH1 mutations are present in about 50% of T-ALL (Asnafi et al., 2009; Mansour, et al., 2007). More than hundred different mutations frequently involved in HD, TAD and PEST domains of NOTCH1 were reported in patients with T-ALL from many researcher groups in different countries (Zhu et al., 2006; Bhanushali et al., 2010; Erbilgin et al., 2010; Mansur et al., 2011). "
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    ABSTRACT: NOTCH families are transmembrane proteins that have dual functions as both cell surface receptors and nuclear transcriptional regulators. If NOTCH1 pathway goes awry, it contributes to cellular transformation and tumorigenesis. Here we have investigated mutations in the NOTCH1 gene, in 50 Iraqi patients with acute lymphoblastic leukemia. We determined the occurrence of mutations in NOTCH1 using HRM-PCR and sequencing of polymerase chain reaction products as a sensitive assay for the detection of genetic mutations. This study assessed the feasibility of using HRM-PCR to screen for NOTCH1 mutations in blood samples obtained by from ALL patients in routine clinical practice. Blood samples obtained from ALL patients were evaluated according to our standard clinical protocols. DNA extracted from these samples was subjected to HRM-PCR to amplify exons 26, 27 and 34 of NOTCH1 followed by sequencing. Mutations were identified in 28% (14/50) of NOTCH1 including two novel mutations. This suggests that NOTCH1 is good prognostic for ALL Iraqi patients. Further studies with a wide range of sampling to confirm these findings are required.
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    • "NOTCH1/FBXW7 mutations were observedin all the genetic subgroups. Although significant differences were not observed inRFS or OS between the NOTCH1/FBXW7 wild-type andmutated cases, as previously described, we noted a trendtoward longer RFS in the mutant patients (Supplemental Figure 1) [10]. Hence, we considered NOTCH1/FBXW7mutation to be a marker of good prognosis and re-analyzedthe survival data for the oncogene expressions. "
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    ABSTRACT: Objective: T-cell acute lymphoblastic leukemia (T-ALL) is associated with recurrent chromosomal aberrations andabnormal ectopic gene expression during T-cell development. In order to gain insight into the pathogenesis of T-ALLthis study aimed to measure the level of expression of 7 T-cell oncogenes (LMO2, LYL1, TAL1, TLX1, TLX3, BMI1, andCALM-AF10) in pediatric T-ALL patients Material and Methods: LMO2, LYL1, TLX1, TLX3, BMI1, TAL1, and CALM-AF10 expression was measured usingquantitative real-time PCR in 43 pediatric T-ALL patients. Results: A high level of expression of LMO2, LYL1, TAL1, and BMI1 genes was observed in a large group of T-ALL.Several gene expression signatures indicative of leukemic arrest at specific stages of normal thymocyte development(LYL1 and LMO2) were highly expressed during the cortical and mature stages of T-cell development. Furthermore,upregulated TAL1 and BMI1 expression was observed in all phenotypic subgroups. In all, 6 of the patients had TLX1and TLX3 proto-oncogene expression, which does not occur in normal cells, and none of the patients had CALM-AF10fusion gene transcription. Expression of LYL1 alone and LMO2-LYL1 co-expression were associated with mediastinalinvolvement; however, high-level oncogene expression was not predictive of outcome in the present pediatric T-ALLpatient group, but there was a trend towards a poor prognostic impact of TAL1 and/or LMO2 and/or LYL1 protooncogeneexpression. Conclusion: Poor prognostic impact of TAL1 and/or LMO2 and/or LYL1 proto-oncogene expression indicate the needfor extensive study on oncogenic rearrangement and immunophenotypic markers in T-ALL, and their relationship totreatment outcome. Conflict of interest:None declared.
    Turkish Journal of Haematology 12/2012; 29(4):325-33. DOI:10.5505/tjh.2012.13540 · 0.36 Impact Factor
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    • "In the present study, we were unable to identify mutation of Notch1 in PEST domain which regulates protein turnover by targeting proteins to the ubiquitin-proteosome complex for subsequent degradation [9,15]. However, a high incidence (4/15 cases) of Notch1 mutation in PEST domain was reported in Indian T-ALL patients [9], while lower incidence was described from a study in Chinese T-ALL patients (5/77, 6.5%) [15], as well as in Turkish patients (7%) and German patients (8.2%) [7,18], the difference may due to the racial diversify. "
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    ABSTRACT: The Notch signaling pathway is crucial in T-cell development, Notch1 mutations are frequently present in T-cell acute lymphoblastic leukemia (T-ALL). To investigate the feature of Notch1 mutation and its corresponding expression level in Chinese patients with T-ALL, detection of mutation and the expression level of Notch1 gene was preformed using RT-PCR, sequencing and real-time PCR respectively. Two Notch1 point mutations (V1578E and L1593P) located on HD-N domain were identified in three cases out of 13 T-ALL patients. The mutation on 4733 position (V1578E) found in two cases was a novel mutation. The overexpression of Notch1 was detected in all samples with T-ALL, moreover, significantly higher expression of Notch1 was detected in the T-ALL with Notch1 mutation group compared with T-ALL with WT Notch1 group (p = 0.0192). Higher expression of Notch1 was associated with Notch1 mutation, more novel mutation of this gene might be identified in different populations and its contribution to the molecular pathogenesis of T-ALL is needed further research.
    Cancer Cell International 04/2012; 12(1):13. DOI:10.1186/1475-2867-12-13 · 2.77 Impact Factor
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