Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. One of the major clinical challenges is adequate diagnosis and treatment of central nervous system (CNS) involvement in this disease. Intriguingly, there is little solid evidence on the mechanisms sustaining CNS disease in ALL. Here, we present and discuss recent data on this topic, which are mainly derived from preclinical model systems. We thereby highlight sites and routes of leukemic CNS infiltration, cellular features promoting infiltration and survival of leukemic cells in a presumably hostile niche, and dormancy as a potential mechanism of survival and relapse in CNS leukemia. We also focus on the impact of ALL cytogenetic subtypes on features associated with a particular CNS tropism. Finally, we speculate on new perspectives in the treatment of ALL in the CNS, including ideas on the impact of novel immunotherapies.

Keywords: Acute lymphoblastic leukemia; Blood-brain-barrier; CNS involvement; Central nervous system; Immunotherapy; Tumor dormancy.

Fig. 1

Potential entry routes and sanctuaries for ALL cells in the CNS. The major locations of CNS involvement in ALL are the meninges consisting of the dura, arachnoid, and pia mater. In the subarachnoid space between arachnoid and pia, ALL cells may either spread or persist as focal lesions in which they may not be detected via lumbar puncture. Entry into the meninges and the subarachnoid space can occur via different routes. Entry from the vasculature into the CNS may occur via the blood brain barrier (BBB) of microvessels in the brain parenchyma (1), the blood leptomeningeal barrier (BLMB) on the surface of the pia mater (2), or the blood cerebrospinal fluid barrier (BCSFB) (3). The BCSFB is situated in the choroid plexus epithelium, which also produces the cerebrospinal fluid (CSF) in the ventricles of the brain. A recent report suggests that ALL cells may avoid these barriers and directly travel into the subarachnoid space along the surface of bridging veins traversing the skull and meninges (4). Moreover, dural lymphatics draining leukocytes out the parenchyma and subarachnoid space may represent an additional route for leukemia cells to enter and leave the subarachnoid space (5)

Fig. 2

Pathways and molecules in CNS infiltration and survival. When reaching the CNS, ALL cells have to cope with a hostile microenvironment. Upregulation of migration/adhesion and survival pathways may cause a particular CNS tropism in ALL cells. Some pathways (1) may be of general relevance for CNS involvement in BCP-ALL. Others may be of particular importance in ALL subtypes with a higher risk for CNS involvement due to their cytogenetic background like E2A-PBX1 (2), BCR-ABL (3), or mixed lineage leukemia-rearrangements (MLLr) (4). Molecules shown to be directly involved in CNS leukemia are marked with a circle (adhesion/migration signaling) or square (survival signaling)