Department 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.
Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany.
Exp Hematol. 2022 Nov;115:30-43. doi: 10.1016/j.exphem.2022.08.005. Epub 2022 Sep 9.
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.
慢性淋巴细胞白血病（CLL）的特征是血液、骨髓和淋巴器官中积累了小而成熟的 CD5+B 淋巴细胞。细胞存活依赖于与白血病微环境的相互作用。然而，控制 CLL 细胞存活的机制仍不完全清楚。巨噬细胞迁移抑制因子（MIF）是一种促炎和免疫调节趋化因子样细胞因子，与主要趋化因子受体 CXCR4 以及单通道 II 型受体 CD74/不变链相互作用。在这项研究中，我们分析了 CXCR4、CD74 和 MIF 在 CLL 中的作用。通过流式细胞术分析血液恶性肿瘤患者的单核细胞中 CXCR4 和 CD74 的共表达。观察到 CLL 患者的 B 细胞上同时存在强烈的 CXCR4 和 CD74 共表达和过表达（n=10）。存活和趋化性测定表明，CXCR4 和 CD74 共同作用以增强 CLL 中恶性细胞的存活和迁移。单独或联合阻断受体促进细胞死亡，并导致鼠类和人类 CLL 细胞中 MIF 驱动的迁移反应被阻断，这表明两个受体的联合激活对于 CLL 细胞的存活和迁移至关重要。这些发现表明，MIF/CXCR4/CD74 轴代表 CLL 中的一个新的治疗靶点。
