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| Página principal > Artículos > Artículos publicados > Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression |
(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Princess Maxima Center for Pediatric Oncology) (Mathematical Oncology Laboratory. Department of Mathematics & amp; Institute of Applied Mathematics in Science and Engineering. Universidad de Castilla-La Mancha) (Centro de Investigación Biomédica en Red de Enfermedades Raras) (Pediatric Hematology and Oncology Department. Hospital Clínico Universitario Virgen de la Arrixaca. Instituto Murciano de Investigación Biosanitaria (IMIB)) (AP-HP. Service of Pediatric Hematology. Hopital Armand Trousseau) (Bambino Gesù Children's Hospital. Catholic University of Sacred Heart) (Department of Pathology. St. Jude Children's Research Hospital) (European Research Institute for the Biology of Aging (ERIBA). University of Groningen. University Medical Center Groningen) (European Research Institute for the Biology of Aging (ERIBA). University of Groningen. University Medical Center Groningen) (Mathematical Oncology Laboratory. Department of Mathematics & amp; Institute of Applied Mathematics in Science and Engineering. Universidad de Castilla-La Mancha) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
| Fecha: | 2024 |
| Resumen: | 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. |
| Ayudas: | Agencia Estatal de Investigación PID2022-142966OB-I00 Instituto de Salud Carlos III RD21/0017/0029 Instituto de Salud Carlos III PI17/01028 Instituto de Salud Carlos III PI20/00822 Agència de Gestió d'Ajuts Universitaris i de Recerca 2022/SGR-003 Ministerio de Ciencia e Innovación 10.13039/501100011033 Agencia Estatal de Investigación PID2019-110895RB-I00 Agencia Estatal de Investigación PID2022-142341OB-I00 Agencia Estatal de Investigación PDC2022-133520-I00 |
| Nota: | 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). |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | Chromosomal instability ; Aneuploidy ; Childhood B-cell acuteLymphoblastic leukemia ; Disease models |
| Publicado en: | EMBO Molecular Medicine, Vol. 16 Núm. 1 (16 2024) , p. 64-92, ISSN 1757-4684 |
