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Editorials
anisms of CNS infiltration in solid tumors and hematologic malignancies likely differ fundamentally. To enter the CNS environment, ALL cells need to pass protective physiologi- cal barriers such as the blood-brain barrier, the blood-lep- tomeningeal barrier and the blood-cerebrospinal fluid barri- er, which in physiological conditions ensure the controlled flux of molecules and passage of cells into the organ.3 The cerebrospinal fluid per se may also represent a hostile envi- ronment for ALL cells due to the limited quantity of pro- teins and the presence of reactive oxygen species.8 The CNS microenvironment may, therefore, critically affect the behavior of ALL cells in this niche.
To investigate the behavior of ALL cells in the CNS, Jonart et al. co-cultured B-cell precursor ALL and T-ALL cell lines as well as primary B-cell precursor ALL cells with pri- mary human meningeal cells, modeling the leptomeningeal microenvironment.5 The authors found that ALL cells effi- ciently adhered to the primary human meningeal cells, ren- dering them less vulnerable to chemotherapy. Therapy sen- sitivity was markedly reduced when ALL cells were grown in direct contact with the meningeal cells and treated with methotrexate and cytarabine, two major compounds of CNS-directed chemotherapy in ALL. Direct contact with primary human meningeal cells also reduced proliferation of ALL cells, leading to the conclusion that chemoresistance was based on the acquisition of a dormant phenotype. Cellular dormancy is a state of transient G0/G1 arrest that may be induced by hostile microenvironments and that may be reversed when cells encounter favorable conditions again.9 Evidence that dormancy may represent a key mech- anism of CNS disease and relapse in ALL is accumulating beyond this work.3 For example, patient-derived xenograft ALL cells recollected from murine meninges were shown to be less proliferative than cells recollected from the bone marrow.10 Furthermore, direct co-culture models of CNS leukemia showed G0/G1 arrest and resistance to methotrex- ate-mediated cytotoxicity in vitro in B-cell precursor ALL in dependence of the receptor tyrosine kinase MER.11 Adhesion processes of leukemia cells to CNS microenviron- mental structures have also recently been shown to play a crucial role in the invasion of leukemia cells into the CNS. Yao et al. showed that the interaction of leukemic cells expressing a6-integrin with laminin on the abluminal sur- face of emissary blood vessels facilitates the cells’ entry into the CNS.12 Furthermore, the chemokine receptor CCR7 was found to promote adhesion and trafficking across the choroid plexus in T-ALL.13 With their recent report, Jonart et al. provide a further piece of the puzzle of CNS leukemia as they show that meningeal cells, presumably the cell entity that ALL cells mostly encounter in the CNS microenviron- ment after invading through the vasculature, promote ALL dormancy, survival and therapy resistance. This observa- tion has important implications for understanding the mechanistic basis of CNS infiltration and relapse in ALL.
The study by Jonart et al. raises the questions of whether the acquisition of dormancy by adhesion to meningeal cells is a feature of every ALL cell in the CNS or whether this is only relevant in a fraction of cells undergoing selection by chemotherapy. Or, if all leukemic cells reaching the CNS adhere to meningeal cells and cease proliferation, how would they then go on to colonize the meninges and be clinically detectable? In their study, Jonart et al. detected a
small, slow cycling fraction of ALL cells recovered from the meninges of xenografted mice. Intriguingly, after treating leukemia-bearing mice with cytarabine, the authors found a 13-fold increase in the number of these quiescent cells whereas only a 5-fold relative increase was found in the bone marrow. This argues in favor of a small fraction of dormant cells that may survive treatment, as previously suggested,14 and in favor of the CNS microenvironment fos- tering the maintenance and enrichment of this fraction. Various molecules and pathways have recently been identi- fied to be associated with CNS infiltration and relapse, some of which are also linked to cellular adhesion: the ZAP70 kinase regulates CXCR4 and CCR7,15 the receptor tyrosine kinase MER exposes structural similarity to neural adhesion molecules11,16 and phosphoinositide-3-kinase was shown to promote integrin-mediated adhesion.12 It would be interesting to investigate whether cells enriching in the CNS after chemotherapy show a particularly high expres- sion of these molecules.
If adhesion-mediated chemoresistance contributes to CNS relapse, how can this concept be exploited to establish novel targeted therapy approaches? One substantial advan- tage of compounds targeting general features such as adhe- sive interactions could be that they act on a variety of ALL cells irrespective of the genetic background. A previous report described promising results obtained from disrupting a6 integrin-laminin interactions via inhibition of phospho- inositide-3-kinase which delayed leukemic CNS engraft- ment in xenograft mouse models. However, the inhibitors used in this study, including idelalisib, which is already in clinical use, were shown to be unable to cross the blood- brain barrier.12 Therefore, such approaches may be effective in preventing the entry of ALL cells into the CNS rather than targeting ALL cells already residing in the CNS.12 CXCR4 is another key molecule associated with homing and adhesion processes in ALL in the CNS.15 The CXCR4 antagonist AMD3100 (plerixafor) reduced leukemia burden in peripheral organs of xenograft mice, but not in the CNS.6 Testing different compounds, Jonart et al. found a high effi- cacy of the small molecule inhibitor Tris[2-(dimethy- lamino)ethyl]amine) (Me6TREN, Me6) in preventing the adhesion of ALL cells to meningeal cells in vitro, thereby restoring their sensitivity to cytarabine. When applied to mice bearing ALL cells, the addition of Me6TREN to cytara- bine treatment resulted in diminished leukemic engraft- ment in the meninges as compared to that following treat- ment with cytarabine alone. Me6TREN was first described as a compound mobilizing hematopoietic progenitor cells from the bone marrow by upregulating matrix metallopro- tease-9 and disrupting the CCL12/CXCR4 axis, thereby outperforming AMD3100.17 Accordingly, compared to AMD3100, Me6TREN showed enhanced efficacy in dis- turbing the adhesion of ALL cells to meningeal cells in the work by Jonart et al.5 Me6TREN has proven to be well tol- erated in mice.17 If Me6TREN is demonstrated to penetrate the CNS in pharmacokinetic and pharmacodynamics stud- ies, this compound could indeed be considered as a drug the for prevention and therapy of CNS disease.
Overall the study by Jonart et al. provokes some interest- ing questions for the future: Do the different cell types in the meninges, e.g., fibroblasts, endothelial cells and peri- cytes, have different impacts on CNS-infiltrating ALL cells?
haematologica | 2020; 105(8)