RT Journal Article
T1 Meningeal leukaemic aggregates as foci of cell expansion and chemoresistance in acute lymphoblastic leukaemia metastasis
A1 Ortiz Sánchez, Paula
A1 Sara González-Soto, 
A1 Luz H Villamizar, 
A1 Valencia Mahón, Jaris
A1 Jiménez Pérez, Eva
A1 Sacedón Ayuso, Rosa
A1 Manuel Ramírez, 
A1 Isabel Fariñas, 
A1 Varas Fajardo, Alberto
A1 Martínez Fernández De Sevilla, Lidia
A1 Vicente López, María Ángeles
AB Purpose: Central nervous system (CNS) involvement and/or relapse remains one of the most important causes of morbidity/mortality in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients. To identify novel therapeutic targets and develop less aggressive therapies, a better understanding of the cellular and molecular microenvironment in leptomeningeal metastases is key. Here, we aimed to investigate the formation of metastatic leptomeningeal aggregates and their relevance to the expansion, survival and chemoresistance acquisition of leukaemia cells.Methods: We used BCP-ALL xenograft mouse models, combined with immunohistofluorescence and flow cytometry, to study the development of CNS metastasis and the contribution of leptomeningeal cells to the organisation of leukaemic aggregates. To in vitro mimic the CNS metastasis, we established co-cultures of three-dimensional (3D) ALL cell spheroids and human leptomeningeal cells (hLMCs) and studied the effects on gene expression, proliferation, cytokine production, and chemoresistance.Results: In xenografted mice, ALL cells infiltrated the CNS at an early stage and, after crossing an ER-TR7+ fibroblast-like meningeal cell layer, they proliferated extensively and formed large vascularised leukaemic aggregates supported by a network of podoplanin+ leptomeningeal cells. In leukaemia spheroid-hLMC co-cultures, unlike conventional 2D co-cultures, meningeal cells strongly promoted the proliferation of leukaemic cells and generated a pro-inflammatory microenvironment. Furthermore, in 3D cell aggregates, leukaemic cells also developed chemoresistance, at least in part due to ABC transporter up-regulation.Conclusion: Our results provide evidence for the formation of metastatic ALL-leptomeningeal cell aggregates, their pro-inflammatory profile and their contribution to leukaemic cell expansion, survival and chemoresistance in the CNS.
PB Springer Nature
YR 2025
FD 2025-02-12
LK https://hdl.handle.net/20.500.14352/129997
UL https://hdl.handle.net/20.500.14352/129997
LA eng
NO Ortiz-Sánchez, P., González-Soto, S., Villamizar, L. H., Valencia, J., Jiménez, E., Sacedón, R., Ramírez, M., Fariñas, I., Varas, A., Fernández-Sevilla, L. M., & Vicente, Á. (2025). Meningeal leukaemic aggregates as foci of cell expansion and chemoresistance in acute lymphoblastic leukaemia metastasis. Cellular Oncology, 48(3), 725-741. https://doi.org/10.1007/S13402-025-01043-Y
NO Spanish Ministry of Science and Innovation
NO European Union (NextGeneration EU)
NO FEDER, UE
NO Carlos III Health Institute
NO Complutense University
NO Minciencias, Colombia
DS Docta Complutense
RD 20 ene 2026