title: Identification of novel NOTCH1 mutations: increasing our knowledge of the NOTCH signaling pathway.
abstract: BACKGROUND
  Alterations in the NOTCH1 signaling pathway are found in about 60% of pediatric T-ALL, but its impact on prognosis remains unclear.
  
  
  METHODS
  We extended the previously published CoALL cohort (n = 74) to a larger cohort (n = 127) and additionally included 38 Argentine patients from ALL IC-BFM to potentially identify novel mutations and decipher a stronger discriminatory effect on the genotype/phenotype relationship with regard to early treatment response and long-term outcome.
  
  
  RESULTS
  Overall, 101 out of 165 (61.2%) T-ALL samples revealed at least one NOTCH1 mutation, 28 of whom had combined NOTCH1 and FBXW7 mutations. Eight T-ALL samples (4.8%) exclusively revealed FBXW7 mutations. Fifty-six T-ALL (33.9%) exhibited a wild-type configuration of either gene. Four novel NOTCH1 mutations were identified localized in the C-terminal PEST domain, in the rarely affected LNR repeat domain and in the ankyrin domain. Novel LNR mutations may contribute to a better understanding of the structure of the NOTCH1 negative regulatory region (NRR) and the R1946 mutation in the ankyrin domain may represent an unusual loss-of-function mutation.
  
  
  CONCLUSIONS
  Overall, NOTCH1 pathway mutations did not affect the relapse rate and outcome of the extended T-ALL cohort uniformly treated according to CoALL protocols, although NOTCH1 mutations were associated with good response to induction therapy (P = 0.009). Individually, HD and PEST domain mutations might exert distinct functional effects on cellular homeostasis under treatment NOTCH1 pathway activity with prognostic implications.
authors.affiliation: Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Gallo Llorente
authors.forename: H
authors.initials: H
authors.lastname: Luther
authors.forename: R
authors.initials: R
authors.lastname: Schneppenheim
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.forename: M
authors.initials: M
authors.lastname: Felice
authors.forename: M A
authors.initials: MA
authors.lastname: Horstmann
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005838:Genotype; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000628:therapy; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; 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
keywords: FBXW7; HD domain; NOTCH1; PEST domain; ankyrin domain; pediatric T-ALL