Molina, ÒscarOrtega-Sabater, CarmenThampi, NamithaFernandez Fuentes, NarcísGuerrero-Murillo, MercedesMartínez-Moreno, AlbaVinyoles, MeritxellVelasco-Hernandez, TaliaBueno, ClaraTrincado, Juan L..Granada, IsabelCampos, DianaGiménez, CarlesBoer, Judith M.Den Boer, Monique L.Fernández Calvo, GabrielCamós Guijosa, MireiaFuster, José LuisVelasco, PabloBallerini, PaolaLocatelli, FrancoMullighan, Charles G.Spierings, Diana C.J.Foijer, FlorisPérez-García, Víctor M.Menéndez, Pablo2025-02-052025-02-052023-11-151757-4676https://hdl.handle.net/2445/218526Chromosomal 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.29 p.application/pdfengcc-by (c) Molina, O. et al., 2023http://creativecommons.org/licenses/by/4.0/AnimalsLeucèmiaAnomalies cromosòmiquesInfantsAnimalsLeukemiaChromosome abnormalitiesChildreninfo:eu-repo/semantics/article7527212025-02-05info:eu-repo/semantics/openAccess38177531