Hyperdiploidy impairs fetal hematopoietic progenitor fitness and differentiation enabling persistence of rare preleukemic aneuploid clones
Year: 2026
Type: article
Abstract: Aneuploidy is a hallmark of cancer but often reduces cellular fitness. In childhood B cell acute lymphoblastic leukemia (cB-ALL), hyperdiploidy is the most common cytogenetic abnormality and arises in utero from early hematopoietic stem/progenitor cells (HSPCs), yet its impact on early hematopoiesis remains unclear. We model two proposed routes to hyperdiploidy, chromosome mis-segregation and cytokinesis failure, by transiently exposing human fetal liver-derived HSPCs to reversine or cytochalasin D. Induced hyperdiploidy impaired fitness and delayed differentiation in vitro, causing hyperdiploid cells to be rapidly outcompeted by euploid counterparts. Nonetheless, hyperdiploid cells engrafted immunodeficient mice, where rare clones persisted long term and acquired non-random chromosomal gains frequently observed in cB-ALL. Despite this persistence, they did not initiate leukemia. These findings support a two-step model in which hyperdiploid fetal clones require additional perinatal/postnatal events for malignant transformation. Our work establishes a valuable human model for studying early aneuploidy-driven events in childhood leukemia.
Source: Cell Reports
Institutions: Instituto de Salud Carlos III, Josep Carreras Leukaemia Research Institute, Universitat de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat Autònoma de Barcelona, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Cáncer, Institut Català d'Oncologia, University Medical Center Groningen, University of Groningen, Institució Catalana de Recerca i Estudis Avançats, Institut de Recerca Sant Joan de Déu
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Leuka, Centres de Recerca de Catalunya, European Commission, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Ministerio de Economía y Competitividad, José Carreras Leukämie-Stiftung, Universitat de Barcelona, Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España, Instituto de Salud Carlos III, European Regional Development Fund, NextGenerationEU
OpenAlex ID: W7141699256