CXCR4 and CD74 together enhance cell survival in response to macrophage migration-inhibitory factor in chronic
Tharshika Thavayogarajah1, Dzmitry Sinitski2, Omar El Bounkari2
1Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany; Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany; Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
Abstract:
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of small, mature CD5+ B lymphocytes in the blood, marrow, and lymphoid organs. Cell survival depends on interaction with the leukemic microenvironment. However, the mechanisms controlling CLL cell survival are still incompletely understood. Macrophage migration-inhibitory factor (MIF), a pro-inflammatory and immunoregulatory chemokine-like cytokine, interacts with CXCR4, a major chemokine receptor, as well as with CD74/invariant chain, a single-pass type II receptor. In this study, we analyzed the roles of CXCR4, CD74, and MIF in CLL. Mononuclear cells from patients with hematological malignancies were analyzed for coexpression of CXCR4 and CD74 by flow cytometry. Strong co- and overexpression of CXCR4 and CD74 were observed on B cells of CLL patients (n = 10). Survival and chemotaxis assays indicated that CXCR4 and CD74 work together to enhance the survival and migration of malignant cells in CLL. Blockade of the receptors, either individually or in combination, promoted cell death and led to an abrogation of MIF-driven migration responses in murine and human CLL cells, suggesting that joint activation of both receptors is crucial for CLL cell survival and mobility. These findings indicate that the MIF/CXCR4/CD74 axis represents a novel therapeutic target in CLL.
