title: Prognostic implications of mutations in NOTCH1 and FBXW7 in childhood T-ALL treated according to the NOPHO ALL-1992 and ALL-2000 protocols.
abstract: BACKGROUND
  In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.
  
  
  METHODS
  We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.
  
  
  RESULTS
  Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P = 0.14) or event-free survival (EFS) (P = 0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.2 ± 1.9 (mean ± SEM), MYB 8.7 ± 0.8 (mean ± SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 ± 0.7, MYB 5.1 ± 1.2, P = 0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P = 0.02) and EFS (P = 0.028) was seen.
  
  
  CONCLUSIONS
  Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated.
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Fogelstrand
authors.forename: Anna
authors.initials: A
authors.lastname: Staffas
authors.forename: Carina
authors.initials: C
authors.lastname: Wasslavik
authors.forename: Helene
authors.initials: H
authors.lastname: Sjögren
authors.forename: Stefan
authors.initials: S
authors.lastname: Söderhäll
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Frost
authors.forename: Erik
authors.initials: E
authors.lastname: Forestier
authors.forename: Sofie
authors.initials: S
authors.lastname: Degerman
authors.forename: Mikael
authors.initials: M
authors.lastname: Behrendtz
authors.forename: Jesper
authors.initials: J
authors.lastname: Heldrup
authors.forename: Kristina
authors.initials: K
authors.lastname: Karrman
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.forename: Jonas
authors.initials: J
authors.lastname: Abrahamsson
authors.forename: Lars
authors.initials: L
authors.lastname: Palmqvist
mesh_terms: D000293:Adolescent; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; 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; D020570:Genes, myb; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D000072056:Transcription Factor HES-1; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; D044767:Ubiquitin-Protein Ligases; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; C078493:HES1 protein, human
keywords: FBXW7; NOTCH1; cytogenetics and molecular genetics; pediatric acute lymphoblastic leukemia; prognosis