title: NOTCH1 and FBXW7 mutations favor better outcome in pediatric South Indian T-cell acute lymphoblastic leukemia.
abstract: The NOTCH1 signaling pathway is essential for hematopoiesis and a critical regulatory step for T-cell proliferation and maturation. The E3 ubiquitin ligase FBXW7 controls NOTCH1 protein stability. Mutations in NOTCH1/FBXW7 activate NOTCH signaling and are of prognostic significance in patients with T-cell acute lymphoblastic leukemia (T-ALL). In this study we analyzed NOTCH1 and FBXW7 mutations in 50 South Indian T-ALL patients treated by a modified ALL BFM 95 regimen. The hot spot exons (HD-N, HD-C, TAD, and PEST) of NOTCH1 and exons 9 of the 10 of FBXW7 were polymerase chain reaction amplified and sequenced. In total, 20 of the 50 (40%) T-ALL patients revealed heterozygous mutations in the NOTCH1 domains, and a predominance of missense mutations in HD-N (70%) and PEST (15%) domains. FBXW7 mutations were detected in 5 of the 50 (10%) T-ALL patients. T-ALL patients with NOTCH1/FBXW7 mutations expressed higher protein level of NOTCH1 compared with patients without NOTCH1/FBXW7 mutations. Six of the mutations detected in NOTCH1 were not reported previously. When tested in a Dual Luciferase Renilla reporter assay some of these conferred increased NOTCH activity, suggesting that these are activating mutations. Importantly, 13 of the 20 (65%) NOTCH1/FBXW7-mutated T-ALL patients showed a good prednisone response (P=0.01) and a better clinical outcome compared with NOTCH1/FBXW7 nonmutated patients (P=0.03). These data suggest that NOTCH1/FBXW7 mutations are present in T-ALL patients from Southern India and may be useful biomarkers to predict prognosis in T-ALL.
authors.affiliation: Departments of *Molecular Oncology ‡Medical Oncology, Cancer Institute (WIA), Chennai, Tamilnadu, India †Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Valliyammai
authors.initials: V
authors.lastname: Natarajan
authors.forename: Obul R
authors.initials: OR
authors.lastname: Bandapalli
authors.forename: Thangarajan
authors.initials: T
authors.lastname: Rajkumar
authors.forename: Tenali Gnana
authors.initials: TG
authors.lastname: Sagar
authors.forename: Nirmala
authors.initials: N
authors.lastname: Karunakaran
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases