白血病
脑膜
癌症研究
阿糖胞苷
生物
免疫学
造血
急性白血病
医学
干细胞
细胞生物学
神经科学
作者
Leslie M. Jonart,Maryam Ebadi,Patrick Basile,K.A. Johnson,Jessica Makori,Peter M. Gordon
出处
期刊:Haematologica
[Ferrata Storti Foundation]
日期:2019-10-17
卷期号:105 (8): 2130-2140
被引量:22
标识
DOI:10.3324/haematol.2019.230334
摘要
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.
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