The choroid plexus stroma constitutes a sanctuary for paediatric B‐cell precursor acute lymphoblastic leukaemia in the central nervous system

Abstract

Despite current central nervous system‐directed therapies for childhood B‐cell precursor acute lymphoblastic leukaemia, relapse at this anatomical site still remains a challenging issue. Few reports have addressed the study of the specific cellular microenvironments which can promote the survival, quiescence, and therefore chemoresistance of B‐cell precursor acute lymphoblastic leukaemia cells in the central nervous system. Herein, we showed by immunofluorescence and electron microscopy that in xenotransplanted mice, leukaemic cells infiltrate the connective tissue stroma of the choroid plexus, the brain structure responsible for the production of cerebrospinal fluid. The ultrastructural study also showed that leukaemia cells are able to migrate through blood vessels located in the choroid plexus stroma. In short‐term co‐cultures, leukaemic cells established strong interactions with human choroid plexus fibroblasts, mediated by an increased expression of ITGA4 (VLA‐4)/ITGAL (LFA‐1) and their ligands VCAM1/ICAM1. Upon contact with leukaemia cells, human choroid plexus fibroblasts acquired a cancer‐associated fibroblast phenotype, with an increased expression of α‐SMA and vimentin as well as pro‐inflammatory factors. Human choroid plexus fibroblasts also have the capacity to reduce the proliferative index of leukaemic blasts and promote their survival and chemoresistance to methotrexate and cytarabine. The inhibition of VLA‐4/VCAM‐1 interactions using anti‐VLA‐4 antibodies, and the blockade of Notch signalling pathway by using a γ‐secretase inhibitor partially restored chemotherapy sensitivity of leukaemia cells. We propose that the choroid plexus stroma constitutes a sanctuary for B‐cell precursor acute lymphoblastic leukaemia cells in the central nervous system. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Infant leukaemia – faithful models, cell of origin and the niche

“…Moreover, co-culture with choroid plexus fibroblasts protected the leukaemic cells when exposed to methotrexate or cytarabine, drugs commonly used in treating CNS leukaemia in infant and paediatric patients. Overall, these findings suggest that the choroid plexus, specifically the fibroblasts within this structure, forms part of the CNS leukaemia niche and is important in facilitating leukaemia cell survival at this site ( Fernández-Sevilla et al, 2020 ). In particular, the study scratches the surface of two important considerations.…”

“…The choroid plexus is responsible for CSF production and a key element of the blood-CSF barrier. Fernández-Sevilla et al recently showed that ALL cells infiltrate the choroid plexus in a murine xenograft model ( Fernández-Sevilla et al, 2020 ). They demonstrated that B-cell precursor ALL cells and human choroid plexus fibroblasts interact in vitro , mediated by reciprocal expression of adhesion molecules, and that choroid plexus fibroblasts acquire a cancer-associated fibroblast phenotype.…”

Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives

“…On the other hand, the treatment with GSI-XII, DAPT, and the blocking antibody against Notch4 in B-ALL potentiated the anti-viability and pro-apoptotic effects of cytarabine in an ROS-dependent way. In addition, the co-administration of GSI-XII and cytarabine lowered the bone marrow leukemic burden in a murine xenograft model of B-ALL [564], while DAPT reduced central nervous system infiltration in a B-ALL murine model and led to increased chemosensitivity of leukemic cells to Ara-C by impairing their interaction with choroid plexus stroma expressing high levels of Jagged1 and ADAM10 [565].…”

Metabolic Reprogramming and Cell Adhesion in Acute Leukemia Adaptation to the CNS Niche

“…Importantly, disruption of the meningeal ALL adhesion with tMe6TREN ethyl]amine) increased the efficacy of chemotherapy in the CNS in leukemia xenograft murine models (Jonart et al, 2020). Other studies demonstrated that B-ALL cells from children and B-ALL cell lines were adherent to astrocytes, choroid plexus fibroblasts, and epithelial cells, thus promoting leukemic cell survival and chemoresistance (Akers et al, 2011;Fernández-Sevilla et al, 2020).…”