CD84 is a survival receptor for CLL cells

• Published in: Oncogene Vol. 33; no. 8; pp. 1006 - 1016
• Main Authors: Binsky-Ehrenreich, I, Marom, A, Sobotta, M C, Shvidel, L, Berrebi, A, Hazan-Halevy, I, Kay, S, Aloshin, A, Sagi, I, Goldenberg, D M, Leng, L, Bucala, R, Herishanu, Y, Haran, M, Shachar, I
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.02.2014; Nature Publishing Group
• Subjects: 631/80/86; 692/420/755; 692/699/67/1990/283/1895; Analysis; Antigens, CD - physiology; Antigens, Differentiation, B-Lymphocyte - immunology; Apoptosis; Base Sequence; Bcl-2 protein; Bone marrow; Case-Control Studies; CD5 antigen; Cell activation; Cell Biology; Cell death; Cell Line, Tumor; Cell surface; Cell Survival; Chronic lymphocytic leukemia; DNA Primers; Gene therapy; Genetic aspects; Health aspects; Histocompatibility Antigens Class II - immunology; Human Genetics; Humans; Internal Medicine; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukocyte migration; Lymphatic leukemia; Lymphocyte receptors; Lymphocytes B; Macrophage migration inhibitory factor; Mcl-1 protein; Medicine; Medicine & Public Health; mRNA; Oncology; original-article; Peripheral blood; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Signaling Lymphocytic Activation Molecule Family; Survival analysis; T cells; Israel; CD74; apoptosis; CD84; MIF; survival
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/onc.2013.31

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B lymphocytes in peripheral blood, lymphoid organs and bone marrow. The main feature of the disease is accumulation of the malignant cells due to decreased apoptosis. CD84 belongs to the signaling lymphocyte activating molecule family of immunoreceptors, and has an unknown function in CLL cells. Here, we show that the expression of CD84 is significantly elevated from the early stages of the disease, and is regulated by macrophage migration inhibitory factor and its receptor, CD74. Activation of cell surface CD84 initiates a signaling cascade that enhances CLL cell survival. Both downmodulation of CD84 expression and its immune-mediated blockade induce cell death in vitro and in vivo . In addition, analysis of samples derived from an on-going clinical trial, in which human subjects were treated with humanized anti-CD74 (milatuzumab), shows a decrease in CD84 messenger RNA and protein levels in milatuzumab-treated cells. This downregulation was correlated with reduction of Bcl-2 and Mcl-1 expression. Thus, our data show that overexpression of CD84 in CLL is an important survival mechanism that appears to be an early event in the pathogenesis of the disease. These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.