title: Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia.
abstract: Activating mutations of the transmembrane receptor NOTCH1 are common in precursor T-cell lymphoblastic leukemia (T-ALL). We systematically analyzed the impact of activating NOTCH1 mutations on early treatment response and long-term outcome in 157 patients with T-ALL of the pediatric ALL-Berlin-Frankfurt-Munster (BFM) 2000 study. We confirm previous results that NOTCH1 mutations occur in more than 50% of T-ALL in children. In 82 patients (82/157; 52.2%), activating NOTCH1 mutations were identified either in the heterodimerization (55/82; 67.1%), in the PEST (13/82; 15.9%), or in both domains (14/82; 17.0%). The presence of NOTCH1 mutations was significantly correlated with a good prednisone response and favorable minimal residual disease (MRD) kinetics, which was independent from sex, age, white blood cell count, and T-cell immunophenotype at the time of diagnosis. Furthermore, activating NOTCH1 mutations specified a large subgroup of patients with an excellent prognosis. These findings indicate that in the context of the ALL-BFM 2000 treatment strategy, NOTCH1 mutations predict a more rapid early treatment response and a favorable long-term outcome in children with T-ALL.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Stephen
authors.initials: S
authors.lastname: Breit
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Thomas
authors.initials: T
authors.lastname: Flohr
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Ludwig
authors.forename: Gabriele
authors.initials: G
authors.lastname: Tolle
authors.forename: Margit
authors.initials: M
authors.lastname: Happich
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D000293:Adolescent; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001215:Asparaginase / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003630:Daunorubicin / Q000008:administration & dosage; D019281:Dimerization; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D009154:Mutation; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D011241:Prednisone / Q000008:administration & dosage; D051881:Receptor, Notch1 / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D018931:Antineoplastic Agents, Hormonal; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D014750:Vincristine; D001215:Asparaginase; D011241:Prednisone; D003630:Daunorubicin