title: The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia.
abstract: BACKGROUND
  PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors.
  
  
  METHODS
  The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols.
  
  
  RESULTS
  PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005).
  
  
  CONCLUSIONS
  PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Zuurbier
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: Maartje J
authors.initials: MJ
authors.lastname: Vuerhard
authors.forename: Valerie
authors.initials: V
authors.lastname: Calvert
authors.forename: Clarissa
authors.initials: C
authors.lastname: Kooi
authors.forename: Jessica G C A M
authors.initials: JG
authors.lastname: Buijs-Gladdines
authors.forename: Willem K
authors.initials: WK
authors.lastname: Smits
authors.forename: Edwin
authors.initials: E
authors.lastname: Sonneveld
authors.forename: Anjo J P
authors.initials: AJ
authors.lastname: Veerman
authors.forename: Willem A
authors.initials: WA
authors.lastname: Kamps
authors.forename: Martin
authors.initials: M
authors.lastname: Horstmann
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics; D015996:Survival Rate
chemical_list: D004273:DNA, Neoplasm; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human