Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance

作者：Tasneem Khanam, Sarah Sandmann, Jochen Seggewiß, Charlotte Ruether, Martin Zimmermann, Allison B. Norvil, Christoph Bartenhagen, Gerrit Randau, Stephanie Mueller, Heidi Herbrueggen, Per Hoffmann, Stefan Herms, Lanying Wei, Marius Woeste, Christian Wuensch, Humaira Gowher, Ilske Oschlies, Wolfram Klapper, Wilhelm Woessmann, Martin Dugas, Birgit Burkhardt · 发表于：Blood · 年份：2020 · DOI：10.1182/blood.2020005381 · 被引用次数：62 · 研究领域：Lymphoma Diagnosis and Treatment、Acute Lymphoblastic Leukemia research、CAR-T cell therapy research

T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. The dismal outcomes (15%-30%) after T-LBL relapse warrant establishing risk-based treatment. To our knowledge, this study presents the first comprehensive, systematic, integrated, genome-wide analysis including relapsed cases that identifies molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as the putative driver for T-LBL. An activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitute the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47% ± 17% in patients with KMT2D mutations, compared with 14% ± 3% in wild-type KMT2D. Structural analysis of the mutated domains of KMT2D revealed a plausible impact on structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL, including high translational potential. The ongoing LBL 2018 trial (www.clinicaltrials.gov #NCT04043494) allows for prospective validation and subsequent fine tuning of the stratification criteria for T-LBL risk groups to improve survival of pediatric patients.