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...

Descripción completa

Detalles Bibliográficos
Autores: Molina, Òscar, Ortega-Sabater, Carmen, Thampi, Namitha, Fernandez Fuentes, Narcís, Guerrero-Murillo, Mercedes, Martínez-Moreno, Alba, Vinyoles, Meritxell, Velasco-Hernandez, Talia, Bueno, Clara, Trincado, Juan L.., Granada, Isabel, Campos, Diana, Giménez, Carles, Boer, Judith M., Den Boer, Monique L., Fernández Calvo, Gabriel, Camós Guijosa, Mireia, Fuster, José Luis, Velasco, Pablo, Ballerini, Paola, Locatelli, Franco, Mullighan, Charles G., Spierings, Diana C.J., Foijer, Floris, Pérez-García, Víctor M., Menéndez, Pablo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/218526
Acceso en línea:https://hdl.handle.net/2445/218526
Access Level:acceso abierto
Palabra clave:Animals
Leucèmia
Anomalies cromosòmiques
Infants
Leukemia
Chromosome abnormalities
Children
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.

Similares en LA Referencia