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.
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 leukemiapatient cohort (n=146) treated on DCOG or COALL protocols. RESULTS:PTEN and AKTE17K 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 leukemiapatients 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 leukemiapatients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors.
Authors: Andrew P Weng; Adolfo A Ferrando; Woojoong Lee; John P Morris; Lewis B Silverman; Cheryll Sanchez-Irizarry; Stephen C Blacklow; A Thomas Look; Jon C Aster Journal: Science Date: 2004-10-08 Impact factor: 47.728
Authors: W A Kamps; J P Bökkerink; K Hählen; J Hermans; H Riehm; H Gadner; M Schrappe; R Slater; E van den Berg-de Ruiter; L A Smets; G A de Vaan; R S Weening; J F van Weerden; E R van Wering; A den der Does-van den Berg Journal: Blood Date: 1999-08-15 Impact factor: 22.113
Authors: Jose Roman-Gomez; Antonio Jimenez-Velasco; Xabier Agirre; Felipe Prosper; Anabel Heiniger; Antonio Torres Journal: J Clin Oncol Date: 2005-10-01 Impact factor: 44.544
Authors: Helga B Salvesen; Ingunn Stefansson; Ellen I Kretzschmar; Paula Gruber; Nicola D MacDonald; Andy Ryan; Ian J Jacobs; Lars A Akslen; Soma Das Journal: Int J Oncol Date: 2004-12 Impact factor: 5.650
Authors: S T Balbach; O Makarova; B R Bonn; M Zimmermann; M Rohde; I Oschlies; W Klapper; C Rössig; B Burkhardt Journal: Leukemia Date: 2015-07-28 Impact factor: 11.528
Authors: Mariaelena Pierobon; Corinne Ramos; Shukmei Wong; K Alex Hodge; Jessica Aldrich; Sara Byron; Stephen P Anthony; Nicholas J Robert; Donald W Northfelt; Mohammad Jahanzeb; Linda Vocila; Julia Wulfkuhle; Guido Gambara; Rosa I Gallagher; Bryant Dunetz; Nicholas Hoke; Ting Dong; David W Craig; Massimo Cristofanilli; Brian Leyland-Jones; Lance A Liotta; Joyce A O'Shaughnessy; John D Carpten; Emanuel F Petricoin Journal: Clin Cancer Res Date: 2017-04-26 Impact factor: 12.531
Authors: E Waanders; B Scheijen; M C J Jongmans; H Venselaar; S V van Reijmersdal; A H A van Dijk; A Pastorczak; R D A Weren; C E van der Schoot; M van de Vorst; E Sonneveld; N Hoogerbrugge; V H J van der Velden; B Gruhn; P M Hoogerbrugge; J J M van Dongen; A Geurts van Kessel; F N van Leeuwen; R P Kuiper Journal: Leukemia Date: 2016-10-13 Impact factor: 11.528
Authors: Joachim B Kunz; Tobias Rausch; Obul R Bandapalli; Juliane Eilers; Paulina Pechanska; Stephanie Schuessele; Yassen Assenov; Adrian M Stütz; Renate Kirschner-Schwabe; Jana Hof; Cornelia Eckert; Arend von Stackelberg; Martin Schrappe; Martin Stanulla; Rolf Koehler; Smadar Avigad; Sarah Elitzur; Rupert Handgretinger; Vladimir Benes; Joachim Weischenfeldt; Jan O Korbel; Martina U Muckenthaler; Andreas E Kulozik Journal: Haematologica Date: 2015-08-20 Impact factor: 9.941
Authors: A Margarida Gomes; Maria V D Soares; Patrícia Ribeiro; Joana Caldas; Vanda Póvoa; Leila R Martins; Alice Melão; Ana Serra-Caetano; Aida B de Sousa; João F Lacerda; João T Barata Journal: Haematologica Date: 2014-02-21 Impact factor: 9.941
Authors: Obul R Bandapalli; Martin Zimmermann; Corinne Kox; Martin Stanulla; Martin Schrappe; Wolf-Dieter Ludwig; Rolf Koehler; Martina U Muckenthaler; Andreas E Kulozik Journal: Haematologica Date: 2013-01-24 Impact factor: 9.941