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CD84 is a survival receptor for CLL cells

Oncogene volume 33, pages 1006–1016 (2014)Cite this article

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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.

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Acknowledgements

The authors gratefully acknowledge members of the Shachar laboratory team for helpful discussions. This research was supported by the Israel Science Foundation, the Israel Cancer Association, The Gurwin Foundation, Israel Cancer Research Foundation (ICRF), the NIH and the Alliance for Lupus Research (RB, LL), and in part by USPHS grant PO1-CA103985 from the National Cancer Institute, NIH (DMG), and by the United Israel Appeal of Canada. I Shachar is the incumbent of the Dr Morton and Ann Kleiman Professorial Chair.

Author contribution: IB-E designed and performed most of the experiments, analyzed results, wrote the paper. AM designed and performed some of the experiments, analyzed results, participated in writing the paper. MCS designed and performed some of the experiments, analyzed results, participated in writing the paper. LS provided reagents, participated in designing the clinical protocol. AB supervised some of the experiments. IH-H provided reagents. SK and AA purified reagent. I Sagi provided reagent, discussed some of the results. DMG provided reagents and participated in writing the paper. LL provided reagents. RB provided reagents and participated in writing the paper. YH provided reagents, performed several experiments, discussed some of the results, MH provided reagents, designed and supervised the clinical protocol. I Shachar designed and supervised the experiments, analyzed the results and wrote the paper.

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  1. I Binsky-Ehrenreich and A Marom: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    I Binsky-Ehrenreich, A Marom, M C Sobotta & I Shachar

  2. Hematology Institute, Kaplan Medical Center, Rehovot, Israel

    L Shvidel, A Berrebi & M Haran

  3. Department of Hematology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

    I Hazan-Halevy, S Kay & Y Herishanu

  4. Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    A Aloshin & I Sagi

  5. Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, NJ, USA

    D M Goldenberg

  6. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    L Leng & R Bucala

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  1. I Binsky-Ehrenreich
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Correspondence to I Shachar.

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DMG is a director and stockholder of Immunomedics, Inc., which is developing the hLL1 mAb.

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Binsky-Ehrenreich, I., Marom, A., Sobotta, M. et al. CD84 is a survival receptor for CLL cells. Oncogene 33, 1006–1016 (2014). https://doi.org/10.1038/onc.2013.31

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