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), 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.</p

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), 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.</p

Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression

The authors thank Anthony V Moorman (University of Newcastle, UK) for assistance in recruiting primary samples, Maria Calvo and Gemma Martín (Scientific and Technological Centers, Universitat de Barcelona [CCiTUB]), Angelika Merkel (Bioinformatics Unit, Institut de Recerca Josep Carreras) for computational technical assistance, Eva Borràs and Eduard Sabidó (Proteomics Facility, Universitat Pompeu Fabra/Centre de Regulació Genòmica de Barcelona) for technical assistance on mass spectrometry and proteomic analyses. We thank CERCA program (Generalitat de Catalunya) and the Josep Carreras Foundation-Obra Social La Caixa for core support. Financial support for this work was obtained from the Spanish Ministry of Economy and Competitiveness/European Union NextGenerationEU (PID2022-142966OB-I00) to PM and OM, the Deutsche José Carreras Leukämie-Stiftung (DJCLS 15R/2023) to OM and ISCIII-RICORS-TERAV within the Next Generation EU program (plan de recuperación, transformación y resiliencia) (RICORS, RD21/0017/0029) to PM. Additional funding was provided by the ISCIII (FEDER PI17/01028 and PI20/00822) to CB and the Generalitat de Catalunya (2022/SGR-003) to PM. OM was supported by the Asociación Española contra el Cancer (AECC; INVES211226MOLI). COS and TVH were supported by the AECC (2019-PRED-28372 and INVES223069VELA, respectively). The work of COS, GFC and VMP-G was supported by the Spanish Ministerio de Ciencia e Innovación and the European Union NextGenerationEU/PRTR, MCIN/AEI/10.13039/501100011033 (grant numbers PID2019-110895RB-I00, PID2022-142341OB-I00, TED2021-132296B-C55, PDC2022-133520-I00). PM is an investigator of the Spanish Cell Therapy Cooperative Network (TERCEL).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