1. Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
- Author
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Mónica del Rey, Jesús María Hernández-Rivas, Rocío Benito, Alfonso García de Coca, Ana‐Belén Herrero, Araceli Rubio-Martinez, Julio Dávila‐Valls, Helen Parker, Jonathan C. Strefford, Ana-Eugenia Rodríguez-Vicente, María Hernández-Sánchez, José‐Luis Ordóñez, Sandra Santos-Mínguez, Miguel Quijada-Álamo, Teresa González, J.M. Hernández-Sánchez, Claudia Pérez-Carretero, Jose Angel Hernandez-Rivas, Marta Martín-Izquierdo, Fundación Memoria de D. Samuel Solorzano Barruso, and Instituto de Salud Carlos III
- Subjects
Male ,0301 basic medicine ,Chronic lymphocytic leukemia ,Clone (cell biology) ,next‐generation sequencing ,Medicine (miscellaneous) ,Somatic evolution in cancer ,Pathogenesis ,Mice ,0302 clinical medicine ,CRISPR ,Research Articles ,Aged, 80 and over ,lcsh:R5-920 ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Prognosis ,030220 oncology & carcinogenesis ,Disease Progression ,Molecular Medicine ,Female ,Chromosome Deletion ,lcsh:Medicine (General) ,Research Article ,Adult ,Biology ,chromosomal abnormality ,03 medical and health sciences ,In vivo ,medicine ,Animals ,Humans ,TP53 gene ,Chromosomal abnormality ,neoplasms ,Aged ,CRISPR/Cas9 system ,biomarkers ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,In vitro ,Disease Models, Animal ,030104 developmental biology ,Cell culture ,Mutation ,Next-generation sequencing ,Cancer research ,chronic lymphocytic leukemia ,Tumor Suppressor Protein p53 ,Biomarkers - Abstract
© 2021 The Authors., [Background]: Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established., [Methods]: We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response., [Results]: Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition., [Conclusions]: Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL., Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI15/01471, PI18/01500); Fundación Memoria Don Samuel Solórzano Barruso, Grant/Award Number: RD12/0036/0069
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- 2021
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