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
Affiliations
Linda Zuurbier
1Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Emanuel F. Petricoin
2Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA;3NCI-FDA Clinical Proteomics Program, Food and Drug Administration, Bethesda, MD, USA
Maartje J. Vuerhard
1Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Valerie Calvert
2Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
Clarissa Kooi
1Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Jessica G.C.A.M. Buijs-Gladdines
1Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Willem K. Smits
1Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Edwin Sonneveld
Anjo J.P. Veerman
4Dutch Childhood Oncology Group (DCOG), the Hague, the Netherlands;5Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands
Willem A. Kamps
4Dutch Childhood Oncology Group (DCOG), the Hague, the Netherlands;6Department of Pediatric Oncology, University of Groningen-Beatrix Children’s Hospital, Groningen, the Netherlands
Martin Horstmann
7German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany;8Research Institute Children's Cancer Center Hamburg, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Rob Pieters
1Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Jules P.P. Meijerink
1Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
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/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.
