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. PROCEDURE: 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.
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. PROCEDURE: 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: Chiara Palmi; Angela M Savino; Daniela Silvestri; Ilaria Bronzini; Gunnar Cario; Maddalena Paganin; Barbara Buldini; Marta Galbiati; Martina U Muckenthaler; Cristina Bugarin; Pamela Della Mina; Stefan Nagel; Elena Barisone; Fiorina Casale; Franco Locatelli; Luca Lo Nigro; Concetta Micalizzi; Rosanna Parasole; Andrea Pession; Maria C Putti; Nicola Santoro; Anna M Testi; Ottavio Ziino; Andreas E Kulozik; Martin Zimmermann; Martin Schrappe; Antonello Villa; Giuseppe Gaipa; Giuseppe Basso; Andrea Biondi; Maria G Valsecchi; Martin Stanulla; Valentino Conter; Geertruy Te Kronnie; Giovanni Cazzaniga Journal: Oncotarget Date: 2016-09-13
Authors: Melissa A Burns; Andrew E Place; Kristen E Stevenson; Alejandro Gutiérrez; Suzanne Forrest; Yana Pikman; Lynda M Vrooman; Marian H Harris; Sarah K Hunt; Jane E O'Brien; Barbara L Asselin; Uma H Athale; Luis A Clavell; Peter D Cole; Lisa M Gennarini; Justine M Kahn; Kara M Kelly; Caroline Laverdiere; Jean-Marie Leclerc; Bruno Michon; Marshall A Schorin; Maria Luisa Sulis; Jennifer J G Welch; Donna S Neuberg; Stephen E Sallan; Lewis B Silverman Journal: Pediatr Blood Cancer Date: 2020-10-07 Impact factor: 3.167