2-Arachidonoylglycerol Modulates CXCL12-Mediated Chemotaxis in Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia

SIMPLE SUMMARY: Most lymphoma patients relapse after therapy, mainly due to malignant cells hidden in tissues and protected by different components from the surrounding microenvironment. In this study, we describe the interaction between two important factors from the microenvironment, the biolipid 2-arachidonoylglycerol and the chemokine CXCL12. We specifically aimed at better understanding the role of 2-arachidonoylglycerol in the migration of lymphoma cells, and how it affects the migration towards CXCL12 and specific downstream signaling pathways. 2-arachidonoylglycerol signals through the cannabinoid receptors type 1 and type 2 (CB1 and CB2). CB1 and CB2 are variably expressed in B-cell lymphoma. We demonstrate that 2-arachidonoylglycerol induces migration of B-lymphoma cells via CB1 and CB2. We also provide evidence that the signaling pathways activated by 2-arachidonolglycerol and CXCL12 are cross-talking. ABSTRACT: To survive chemotherapy, lymphoma cells can relocate to protective niches where they receive support from the non-malignant cells. The biolipid 2-arachidonoylglycerol (2-AG), an agonist for the cannabinoid receptors CB1 and CB2, is released by stromal cells in the bone marrow. To investigate the role of 2-AG in lymphoma, we analyzed the chemotactic response of primary B-cell lymphoma cells enriched from peripheral blood of twenty-two chronic lymphocytic leukemia (CLL) and five mantle cell lymphoma (MCL) patients towards 2-AG alone and/or to the chemokine CXCL12. The expression of cannabinoid receptors was quantified using qPCR and the protein levels visualized by immunofluorescence and Western blot. Surface expression of CXCR4, the main cognate receptor to CXCL12, was analyzed by flow cytometry. Phosphorylation of key downstream signaling pathways activated by 2-AG and CXCL12 were measured by Western blot in three MCL cell lines and two primary CLL samples. We report that 2-AG induces chemotaxis in 80% of the primary samples, as well as 2/3 MCL cell lines. 2-AG induced in a dose-dependent manner, the migration of JeKo-1 cell line via CB1 and CB2. 2-AG affected the CXCL12-mediated chemotaxis without impacting the expression or internalization of CXCR4. We further show that 2-AG modulated p38 and p44/42 MAPK activation. Our results suggest that 2-AG has a previously unrecognized role in the mobilization of lymphoma cells by effecting the CXCL12-induced migration and the CXCR4 signaling pathways, however, with different effects in MCL compared to CLL.