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Editorials
When the bond breaks – targeting adhesion of leukemia cells to the meninges
Lennart Lenk, Fotini Vogiatzi and Denis M. Schewe
Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig- Holstein, Kiel, Germany.
E-mail: DENIS M. SCHEWE - Denis.Schewe@uksh.de doi:10.3324/haematol.2020.253609
Amajor clinical challenge in the treatment of acute lymphoblastic leukemia (ALL) is the involvement of the central nervous system (CNS), especially in children. CNS involvement can occur upon initial diagno- sis and be a source of relapse.1 Due to the high propensity of ALL cells to infiltrate the CNS and the lack of specific markers for their detection and eradication, patients receive high cumulative doses of intrathecal chemothera- py. This is associated with neurotoxicity, which may lead to acute complications and long-term developmental delay in children.2 The CNS is regarded as a privileged “niche” in which ALL cells can persist due, for example, to the paucity of immune cells and the blood-brain barrier impairing accessibility of this sanctuary by chemothera- py.3,4 Thus, gaining a deeper understanding of how ALL
cells interact with the CNS microenvironment may open the field for novel targeted approaches to eradicate ALL cells in the CNS. In this issue of Haematologica, Jonart et al. describe how ALL cells seek shelter by adhering to meningeal cells, resulting in quiescence and chemoresis- tance. The authors propose interference with adhesion mechanisms as a novel therapeutic strategy in CNS leukemia5 (Figure 1).
Infiltration of the CNS can be observed in metastasis of solid cancers, as well as in hematologic malignancies including ALL, other leukemias and lymphomas. CNS metastasis of solid cancers mostly affects the brain parenchyma, but ALL cells predominantly reside in the lep- tomeninges, a conjunctive tissue surrounding the parenchy- ma and the ventricular choroid plexus.5–7 Hence, the mech-
Figure 1. Leukemia cells seek shelter by adhering to meningeal cells. Acute lymphoblastic leukemia (ALL) cells breach the blood-leptomeningeal barrier and infiltrate the leptomeninges. They encounter a hostile microenvironment in which nutrients are scarce (cerebrospinal fluid) and levels of reactive oxygen species (ROS) are enhanced. By adhering to meningeal cells, ALL cells acquire a state of reversible quiescence (dormancy) rendering them less vulnerable to chemotherapy. Disrupting the adhesion of ALL cells to meningeal cells via Me6TREN mobilizes ALL cells from the niche, thereby restoring their susceptibility to chemotherapeutic agents.
haematologica | 2020; 105(8)
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