Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance
Leslie M. Jonart,
Maryam Ebadi,
Patrick Basile,
Kimberly Johnson,
Jessica Makori,
Peter M. Gordon
Affiliations
Leslie M. Jonart
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
Maryam Ebadi
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
Patrick Basile
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
Kimberly Johnson
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
Jessica Makori
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
Peter M. Gordon
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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.
