Leukemia-derived exosomes and cytokines pave the way for entry into the brain. Ichiko Kinjyo,1 Denis Bragin,2 Rachel Grattan,1 Stuart S. Winter, 3 and Bridget S. Wilson 1, 4 1Department of Pathology, University of New Mexico, Albuquerque, USA; 2Department of Neurosurgery, University of New Mexico, Albuquerque, USA; 3Blood Diseases and Cancer Program, Children's Hospitals & Clinics of Minnesota, Minneapolis, USA; 4Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, USA
Infiltration of acute lymphoblastic leukemia (ALL) blasts into the central nervous system (CNS) remains as a major clinical problem, with high risk for chemotherapy-resistant relapse and treatment-related morbidity. Despite the common inclusion of CNS prophylaxis treatments in therapy regimens, there are significant gaps in understanding the mechanisms that mediate leukemia blasts entry into the CNS as well as roles for brain resident cells for CNS leukemia pathogenesis. In this study, we employ a xenograft model of human B cell precursor (BCP)-ALL in immunocompromised mice with key pathological characteristics of CNS involvement seen in relapsed/late stage patients. We examined the process of leukemia invasion into CNS and provide evidence that the interaction between blasts and brain resident cells cause aberrant activation of host cells at the brain microenvironment. We found multiple cytokines are released from BCP-ALL blasts, as well as host cells in response to the changing microenvironment. CNS invasion by leukemia cells is linked to the production of VEGF-AA by astrocytes and disruption of the blood-brain-barrier (BBB) integrity. We also found that leukemia blasts release exosomes containing IL-15 that bind and are internalized by astrocytes and brain vessel endothelial cells. Knockdown of either IL-15 or IL-15R in the NALM6 cell line diminishes CNS infiltration in engrafted mice. These results provide important insights into the multiple mechanisms by which lymphoblasts modulate the brain microenvironment to breach BBB for metastatic invasion into brain parenchyma.
Credits: None available.
You must be logged in and own this product in order to