Abstract
Abstract 2694
Recurrence of acute leukemia (AL) in the central nervous system (CNS) confers a poor prognosis. However, little is known about the the underlying mechanisms of leukemic cell infiltration into the CNS. The blood brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. Tight junction in brain microvessel endothelial cells (HMECs) constituted by tight junction proteins is an important structure of BBB. Except the well known role of degrading extracellular matrix in metastasis of cancer cells, here we identify matrix metalloproteinase 2 (MMP-2) and MMP-9 secreted by leukemic cells are also associated with BBB opening by degrading tight junction proteins. We have successfully established an animal model of CNS leukemia by using a highly invasive human acute monocytic leukemia cell line SHI-1 in nude mice. Multiple organs including skull and brain were sectioned and determined histopathologically for leukemia cell infiltration. The fact that the down- regulation of ZO-1, Claun-5 and Occludin accompanied with up-regulation of MMP-2 and MMP-9 was correlated with BBB breakdown in mice with CNS leukemia was found when examined by laser scanning fluorescence confocal microscopy and gelatin in situ zymography. The treatment with MMP-inhibitor GM6001 could significantly reverse these changes in tight junction proteins. In an in vitro monolayer BBB model made by human encephalo-microvessel endothelial cells and matreil gel, MMP-2 and MMP-9 specifically down-regulated ZO-1, Claun-5 and Occludin. Knock-down or inhibition of MMP-2 and MMP-9 expression protected ZO-1, Claun-5 and occludin from degradation and alleviated the permeability of BBB. Our findings suggest that the degradation of tight junction proteins ZO-1, Claun-5 and Occludin by MMP-2 and MMP-9 secreted by leukemic cells constitutes an important mechanism in BBB breakdown in CNS leukemia. These studies provide a potent evidence for future pharmacological treatment to inhibit the CNS involvement in acute leukemia.
Disclosures:
No relevant conflicts of interest to declare.
Interleukin-34 Restores Blood–Brain Barrier Integrity by Upregulating Tight Junction Proteins in Endothelial Cells
