Protection from acute lymphoblastic leukemia relapse in the central nervous system (CNS) is crucial to survival and quality of life for leukemia patients. Current CNS-directed therapies cause significant toxicities and are only partially effective. Moreover, the impact of the CNS microenvironment on leukemia biology is poorly understood. In this study we showed that leukemia cells associated with the meninges of xenotransplanted mice, or co-cultured with meningeal cells, exhibit enhanced chemoresistance due to effects on both apoptosis balance and quiescence. From a mechanistic standpoint, we found that leukemia chemoresistance is primarily mediated by direct leukemia-meningeal cell interactions and overcome by detaching the leukemia cells from the meninges. Next, we used a co-culture adhesion assay to identify drugs that disrupted leukemia-meningeal adhesion. In addition to identifying several drugs that inhibit canonical cell adhesion targets we found that Me6TREN (Tris[2-(dimethylamino)ethyl]amine), a novel hematopoietic stem cell-mobilizing compound, also disrupted leukemia-meningeal adhesion and enhanced the efficacy of cytarabine in treating CNS leukemia in xenotransplanted mice. This work demonstrates that the meninges exert a critical influence on leukemia chemoresistance, elucidates mechanisms of relapse beyond the well-described role of the blood-brain barrier, and identifies novel therapeutic approaches for overcoming chemoresistance.
Bibliographical noteFunding Information:
This work was supported in part by the Children’s Cancer Research Fund (PMG), the Timothy O’Connell Foundation (PMG), and an American Cancer Society Institutional Research Grant (PMG). PB was partially supported by NIH Training Grant T32 CA099936. We thank Dr. Michael Farrar for providing mouse BCR/ABL p190 leukemia cells, Dr. Juan Abrahante Lloréns (University of Minnesota Genomics Center) for assistance with RNA-sequencing data analyses, Dr. Mark Sanders (University of Minnesota Imaging Center) for providing expert assistance with confocal microscopy and sample preparation, and Mike Ehrhardt (University of Minnesota Cytokine Reference Laboratory) for assistance with measuring cytokine levels. This work utilized the University of Minnesota Masonic Cancer Center shared flow cytometry and comparative pathology resources and the Hematological Malignancy Tissue Bank, which are supported in part by NCI 5P30CA077598-18, Minnesota Masonic Charities, and the Killebrew-Thompson Memorial Fund.