The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

Linda Zuurbier, Emanuel F. Petricoin, Maartje J. Vuerhard, Valerie Calvert, Clarissa Kooi, Jessica G.C.A.M. Buijs-Gladdines, Willem K. Smits, Edwin Sonneveld, Anjo J.P. Veerman, Willem A. Kamps, Martin Horstmann, Rob Pieters, Jules P.P. Meijerink

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102 Scopus citations

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. Design and 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/AKTmutations 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.

Original languageEnglish
Pages (from-to)1405-1413
Number of pages9
JournalHaematologica
Volume97
Issue number9
DOIs
StatePublished - 2012
Externally publishedYes

Keywords

  • AKT
  • NOTCH1
  • Outcome
  • PTEN
  • Pediatric T-ALL
  • γ-secretase resistance

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