Prognostic Significance of NOTCH1 and FBXW7 Mutations in Childhood T-Cell Acute Lymphoblastic Leukemia (T-ALL): Results From the EORTC Children Leukemia Group.

作者：Emmanuelle Clappier, Sandra Collette, Nathalie Grardel, Sandrine Girard, Lydia Suarez, Ghislaine Brunie, Sophie Kaltenbach, Karima Yakouben, Françoise Mazingue, Alain Robert, Patrick Boutard, Dominique Plantaz, Pierre‐Simon Rohrlich, Claude Preudhomme, Frank Speleman, Jacques Otten, Nicole Dastugue, Stefan Suciu, Yves Benoît, Yves Bertrand, Hélène Cavé · 发表于：Blood · 年份：2009 · DOI：10.1182/blood.v114.22.909.909 · 被引用次数：3 · 研究领域：Acute Lymphoblastic Leukemia research、Cancer-related gene regulation、Ubiquitin and proteasome pathways

Abstract Abstract 909 T-ALL accounts for approximately 15% of childhood ALL. Despite major improvement of treatments, relapses still occur with dramatic prognosis. Efforts made in the past decade to understand T-ALL oncogenesis led to the identification of a number of oncogenes deregulated by genomic abnormalities, including TAL1, HOX11/TLX1, HOX11L2/TLX3, CALM-AF10, NUP214-ABL1, and MYB, some of them determining subtypes with distinct biological profiles. However, in EORTC trials, using BFM-derived protocols, these various genetic lesions have no prognostic impact, with the exception of a trend toward a favourable outcome for SIL-TAL1 fusion or HOX11 over expression (Cavé et al. 2004). Thus, risk-stratification remained based on early response to chemotherapy, as assessed by poor response to the (corticosteroid) prephase (PPR) and, in addition (58951 trial), on a high level (>10-2) of minimal residual disease (MRD) at completion of induction therapy. Hyperactivation of the NOTCH pathway by mutations of NOTCH1 or FBXW7 has been recently demonstrated in T-ALL. We investigated whether NOTCH1 and/or FBXW7 status could help to improve risk-stratification in T-ALL. We screened NOTCH1 and FBXW7 mutations by direct sequencing in 133 children with T-ALL enrolled in EORTC-CLG trials 58881 and 58951. Activating NOTCH1 mutations were found in 75 (56%) patients. Inactivating FBXW7 mutations were found in 20 (14%) patients, mostly in association with NOTCH1 mutations. Overall, 78 (59%) p...