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CD84 Is a Survival Receptor for CLL Cells

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CD84 Is a Survival Receptor for CLL Cells Oncogene (2014) 33, 1006–1016 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc ORIGINAL ARTICLE CD84 is a survival receptor for CLL cells I Binsky-Ehrenreich1,7, A Marom1,7, MC Sobotta1, L Shvidel2, A Berrebi2, I Hazan-Halevy3,SKay3, A Aloshin4, I Sagi4, DM Goldenberg5, L Leng6, R Bucala6, Y Herishanu3, M Haran2 and I Shachar1 Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5 þ 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. Oncogene (2014) 33, 1006–1016; doi:10.1038/onc.2013.31; published online 25 February 2013 Keywords: CD84; CD74; MIF; survival; apoptosis INTRODUCTION CD84 is a member of the signaling lymphocyte activation Chronic lymphocytic leukemia (CLL) is the most common molecule (SLAM) immunoglobulin superfamily. It is a single- leukemia in the Western world and is characterized by the chain cell-surface protein with a cytoplasmic tail that contains four 13 14,15 progressive accumulation of small mature CD5 þ lymphocytes in tyrosines. CD84 strongly self-associates with a Kd in the the peripheral blood, lymphoid organs and bone marrow (BM). submicromolar range; the association is driven by the Ig-V 16 The main feature of the disease is decreased apoptosis, resulting domain, forming an orthogonal homophilic dimer. The SLAM 17–20 in the pathologic accumulation of these malignant cells.1 Despite family was found to modulate the behavior of immune cells. major progress in the last few years in the understanding of the This seems to be due to the capacity of these receptors to interact biology and pathophysiology of this disease, as well as the with SLAM-associated protein (SAP)-related molecules, a group of development of better treatment modalities, CLL remains SRC homology 2 (SH2) domain adapters. The SAP family is incurable in most patients, and even control of the disease comprised of three members: SAP, Ewing’s sarcoma-associated requires aggressive treatment with significant side effects. CD74 is transcript-2 (EAT-2), and in rodents, EAT-2-related transducer 18,21 a type-II integral membrane protein that was originally thought to (ERT). In humans, the gene encoding ERT has evolved into a function mainly as an major histocompatibility complex class-II non-functional pseudo-gene. SAP does not appear to be chaperone.2 It was shown previously that macrophage migration expressed in B cells; rather EAT-2 is proposed as the functional 22,23 inhibitory factor (MIF) binds to the CD74 extracellular domain, a homolog in these cells. The interaction of the SLAM family process that results in regulating survival of mature murine B receptors with SAP family members is mediated by tyrosine-based cells.3–8 In CLL, CD74 and its ligand MIF were shown to regulate motifs in the cytoplasmic region of SLAM-related receptors, and 23 survival of the leukemic cells. Binding of MIF to CD74 initiates a by the SH2 domain of SAP-related adapters. signaling cascade that can be observed from the very early stages Although CD84 was originally cloned from a human B-cell line of the disease. This pathway induces nuclear factor-kB activation, complementary DNA library, very little is known regarding its resulting in the upregulation of Bcl-2, which in turn promotes cell biology. It was shown recently that CD84 is required for prolonged survival.9–11 Blocking of this pathway by the monoclonal anti- T cell–B cell contact and for optimal T follicular helper function 24 CD74 antibody (mAb) hLL1 (milatuzumab)12 leads to decreased and germinal center formation. Nevertheless, both the cell survival.9,10 To determine the identities of the molecules expression and the function of CD84 in the biology of malignant whose expression is modulated by CD74, thereby regulating CLL B cells remain to be fully explored. survival, we investigated CD74 target genes. One striking example In the current study, we examined the expression and function that we identified (see Results), whose expression was strongly of CD84 in CLL cells. Our results show an elevation of regulated by CD74, is CD84. CD84 expression in CLL cells from early disease stages in a 1Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; 2Hematology Institute, Kaplan Medical Center, Rehovot, Israel; 3Department of Hematology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; 4Biological Regulation, Weizmann Institute of Science, Rehovot, Israel; 5Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, NJ, USA and 6Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA. Correspondence: Dr I Shachar, Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: [email protected] 7These authors contributed equally to this work. Received 19 July 2012; revised 2 January 2013; accepted 2 January 2013; published online 25 February 2013 CD84 is a survival receptor I Binsky-Ehrenreich et al 1007 MIF-CD74-dependent manner. CD84 expression in turn regulates As the expression of CD84 was not characterized previously in the survival of CLL cells in vitro and in vivo. Thus, blocking CD84 CLL, we next determined its expression levels in CLL cells from activity may be a novel therapeutic strategy for interfering with patients at various disease stages. Purified B cells from healthy tumorigenic survival pathways. subjects as well as early- and advanced-stage CLL cells were analyzed for the presence of CD84 messenger RNA (mRNA; targeting a segment common to all isoforms). As shown in Figures 1a and b, low levels of CD84 message were detected in normal B RESULTS cells, whereas elevated levels of CD84 mRNA were observed CD84 expression is elevated in CLL cells in a MIF/CD74-dependent in all the CLL patients, regardless of the stage of disease manner (Supplementary Table 3). Genomic characterization of CD84 To better understand the biological function of CD74 in CLL cells, revealed the existence of five isoforms differing in their we sought to identify target genes induced by CD74 activation. cytoplasmic domains.25 Isoform c was the dominant isoform Thus, CLL cells were incubated in the presence or absence of expressed in CLL cells (data not shown). the CD74 ligand, MIF (100 ng/ml), for 18 h, and RNA from We next compared by flow cytometry the cell surface MIF-stimulated cells was compared with RNA derived from expression levels of CD84 in normal and CLL cells. CD84 cell unstimulated cells using the Affymetrix GeneChip expression surface levels were significantly higher in all CLL cells when analysis system (GSE37430). Many genes were found to be compared with total (Figure 1c; percent and mean fluorescence differentially expressed in these populations; one example was intensity (MFI) and Supplementary Figure 1A) or CD5 þ normal B CD84, whose expression was markedly elevated in the MIF- cells (Figure 1d). These results were observed uniformly in all the induced CLL cells. samples examined, regardless of the clinical parameters of the 3 normal early advanced 2.5 * 2 CD84 1.5 Fold 1 2.92.7 2.9 2.7 2.7 2.8 1 Fold of change in Actin CD84 mRNA level 0.5 Fold1.1 1.11 11 1.1 1 0 normal CLL *p<0.0003 7 4 * 3.5 Normal CLL 6 * 3 20% 89% 5 2.5 4 2 3 1.5 2 1 Fold of change in expression (percent) CD84 MFI expression fold of change in CD84 1 0.5 0 0 CD84 normal CLL normal CLL *p<0.000002 *p<0.0000028 Normal CLL 10 8.5 1.5 69.5 CD84 66 15.5 3 26 CD5 Figure 1. Elevated expression of CD84 in CLL cells. (a) B cells derived from healthy subjects (normal; N ¼ 4), as well as early- (N ¼ 6) and advanced- (N ¼ 6) stage CLL patients were purified and examined for CD84 expression. CD84 and actin mRNA were analyzed by RT–PCR. (b) Quantitative real time (qRT–PCR) was performed using primers for CD84 and RP-2. Results are expressed as fold change in CD84 mRNA in CLL cells compared with normal B cells, which was defined as 1. The graph summarizes results of three normal donors, and seven CLL patients. (c) Histograms show CD84 expression (gray line) or staining with secondary Ab alone (dotted line) in normal B and CLL cells. The graphs summarize the results of 4 normal donors and 18 CLL patients in percent or MFI. (d) Dot plots show CD84 and CD5 expression on CD19-positive cells. Dot plots are representative of N ¼ 3 normal and N ¼ 4 CLL cell samples.
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