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Haematologica 2020 Volume 105(8):2130-2140
Acute Lymphoblastic Leukemia
Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance
Leslie M. Jonart,1,2 Maryam Ebadi,1,2 Patrick Basile,1,2 Kimberly Johnson,1,2 Jessica Makori1,2 and Peter M. Gordon1,2
1Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota and 2Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
ABSTRACT
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, eluci- dates mechanisms of relapse beyond the well-described role of the blood- brain barrier, and identifies novel therapeutic approaches for overcoming chemoresistance.
Introduction
Central nervous system (CNS) relapse is a common cause of treatment failure among patients with acute lymphoblastic leukemia (ALL).1-3 Relapses occur despite CNS-directed therapies which include high-dose systemic chemotherapy, intrathe- cal chemotherapy, and cranial irradiation in some high-risk patients. These current CNS-directed therapies are also associated with significant acute and long-term toxicities.4-10 Accordingly, novel CNS-directed leukemia therapies are needed to improve long-term outcomes in ALL while decreasing treatment-related morbidity.
Historically, the ability of leukemia cells and chemotherapy to access the restrict- ed CNS environment has been posited as a critical factor in the pathophysiology of CNS leukemia and relapse. However, several lines of evidence suggest that this is an overly simplistic model. First, high rates (>50%) of CNS leukemia occur in patients in the absence of adequate CNS-directed therapies as well as in mice trans- planted with human, primary B-cell precursor leukemia cells.11-14 Moreover, clonal analyses of paired leukemia cells isolated from both the bone marrow and CNS of patients and xenotransplanted mice demonstrated that all, or most, B-cell ALL clones are capable of disseminating to the CNS.14,15 Third, CNS leukemia relapses occur despite high-dose systemic and intrathecal chemotherapy. These therapies either overcome or bypass the blood-brain barrier. Fourth, it was shown that high Mer kinase-expressing, t(1;19) leukemia cells co-cultured with CNS-derived cells exhibit G0/G1 cell cycle arrest, suggestive of dormancy or quiescence, as well as
Correspondence:
PETER GORDON,
gord0047@umn.edu
Received: June 24, 2019. Accepted: October 14, 2019. Pre-published: October 17, 2019.
doi:10.3324/haematol.2019.230334
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2130
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