Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance.
Blood
; 137(17): 2347-2359, 2021 04 29.
Article
in En
| MEDLINE
| ID: mdl-33152759
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Biomarkers, Tumor
/
Phosphatidylinositol 3-Kinases
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Genomics
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DNA-Binding Proteins
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Proto-Oncogene Proteins c-akt
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Receptor, Notch1
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/
Neoplasm Proteins
Type of study:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Adolescent
/
Child
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Female
/
Humans
/
Male
Language:
En
Journal:
Blood
Year:
2021
Type:
Article
Affiliation country:
Germany