title: CD84 is a survival receptor for CLL cells.
abstract: 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.
authors: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors: I
authors: I
authors: Binsky-Ehrenreich
authors: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors: A
authors: A
authors: Marom
authors: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors: M C
authors: MC
authors: Sobotta
authors: Hematology Institute, Kaplan Medical Center, Rehovot, Israel.
authors: L
authors: L
authors: Shvidel
authors: Hematology Institute, Kaplan Medical Center, Rehovot, Israel.
authors: A
authors: A
authors: Berrebi
authors: Department of Hematology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors: I
authors: I
authors: Hazan-Halevy
authors: Department of Hematology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors: S
authors: S
authors: Kay
authors: Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: A
authors: A
authors: Aloshin
authors: Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors: I
authors: I
authors: Sagi
authors: Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, NJ, USA.
authors: D M
authors: DM
authors: Goldenberg
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors: L
authors: L
authors: Leng
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors: R
authors: R
authors: Bucala
authors: Department of Hematology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors: Y
authors: Y
authors: Herishanu
authors: Hematology Institute, Kaplan Medical Center, Rehovot, Israel.
authors: M
authors: M
authors: Haran
authors: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors: I
authors: I
authors: Shachar
mesh_terms: D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D017209:Apoptosis; D001483:Base Sequence; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002470:Cell Survival; D017931:DNA Primers; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071176:Signaling Lymphocytic Activation Molecule Family
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C498970:CD84 protein, human; D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D000071176:Signaling Lymphocytic Activation Molecule Family; C045084:invariant chain