Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression

Chromosomal instability (CIN) lies at the core of cancer development leading to aneuploidy, chromosomal copy-number heterogeneity (chr-CNH) and ultimately, unfavorable clinical outcomes. Despite its ubiquity in cancer, the presence of CIN in childhood B-cell acute lymphoblastic leukemia (cB-ALL), th...

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Autores: Molina, Oscar|||0000-0001-7585-4519, Ortega-Sabater, C., Thampi, Namitha|||0000-0001-6166-583X, Fernández Fuentes, Narcís|||0000-0002-6421-1080, Guerrero Murillo, Mercedes|||0000-0002-5556-2460, Martínez Moreno, Alba|||0000-0001-7514-260X, Vinyoles, Meritxell|||0000-0003-1906-4701, Velasco-Hernández, Talia|||0000-0003-2183-7443, Bueno, Clara|||0000-0003-1442-6216, Trincado Alonso, Juan Luis, 1987-|||0000-0001-5363-3774, Granada, Isabel|||0000-0002-4275-0104, Campos, Diana, Giménez, Carles, Boer, Judith M.|||0000-0003-4848-7789, den Boer, Monique L., Calvo, Gabriel F.|||0000-0002-3623-236X, Camós, Mireia|||0000-0003-3658-7942, Fuster, José Luis|||0000-0002-4881-9440, Velasco Puyo, Pablo|||0000-0001-7331-9483, Ballerini, Paola, Locatelli, Franco|||0000-0002-7976-3654, Mullighan, Charles G.|||0000-0002-1871-1850, Spierings, Diana C.J.|||0000-0001-8403-474X, Foijer, Floris|||0000-0003-0989-3127, Pérez-García, Víctor M.|||0000-0002-6575-495X, Menéndez Bujan, Pablo|||0000-0001-9372-1007
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:289549
Acceso en línea:https://ddd.uab.cat/record/289549
https://dx.doi.org/urn:doi:10.1038/s44321-023-00006-w
Access Level:acceso abierto
Palabra clave:Chromosomal instability
Aneuploidy
Childhood B-cell acuteLymphoblastic leukemia
Disease models
Descripción
Sumario:Chromosomal instability (CIN) lies at the core of cancer development leading to aneuploidy, chromosomal copy-number heterogeneity (chr-CNH) and ultimately, unfavorable clinical outcomes. Despite its ubiquity in cancer, the presence of CIN in childhood B-cell acute lymphoblastic leukemia (cB-ALL), the most frequent pediatric cancer showing high frequencies of aneuploidy, remains unknown. Here, we elucidate the presence of CIN in aneuploid cB-ALL subtypes using single-cell whole-genome sequencing of primary cB-ALL samples and by generating and functionally characterizing patient-derived xenograft models (cB-ALL-PDX). We report higher rates of CIN across aneuploid than in euploid cB-ALL that strongly correlate with intraclonal chr-CNH and overall survival in mice. This association was further supported by in silico mathematical modeling. Moreover, mass-spectrometry analyses of cB-ALL-PDX revealed a "CIN signature" enriched in mitotic-spindle regulatory pathways, which was confirmed by RNA-sequencing of a large cohort of cB-ALL samples. The link between the presence of CIN in aneuploid cB-ALL and disease progression opens new possibilities for patient stratification and offers a promising new avenue as a therapeutic target in cB-ALL treatment.

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