Hyperdiploidy impairs fetal hematopoietic progenitor fitness and differentiation enabling persistence of rare preleukemic aneuploid clones

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 <em>in utero</em> from early hematopoietic stem/progenitor cells (HSPCs), yet its impact o...

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Detalles Bibliográficos
Autores: Thampi, Namitha, Calvo, Cristina, Rodríguez Cortez, Virginia Carolina, Martínez-Moreno, Alba, Roca-Ho, Heleia, Vinyoles, Meritxell, Bueno, Clara, Espinosa-Aroca, Lady, Pablo-Fontecha, Verónica, Camps, Jordi, Fuente-González, A. de la, Puente, Xose S, Solé, Francesc, Foijer, Floris, Menéndez Buján, Pablo, Molina, Òscar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2026
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:dnet:ubarcelona__::52319a251b5d5500b385e25d7072a21f
Acceso en línea:https://hdl.handle.net/2445/228727
Access Level:acceso abierto
Palabra clave:Leucèmia limfocítica crònica
Càncer en els infants
Chronic lymphocytic leukemia
Cancer in children
Descripción
Sumario: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 <em>in utero</em> 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 <em>in vitro</em>, 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.

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