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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4683-4689.
Prepublished online as a Blood First Edition Paper on January 23, 2008; DOI 10.1182/blood-2007-04-084525.
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Submitted April 11, 2007
Accepted December 13, 2007
CD27-CD70 interactions in the pathogenesis of Waldenstrom's Macroglobulinemia
Allen W. Ho, Evdoxia Hatjiharissi, Bryan T. Ciccarelli, Andrew R. Branagan, Zachary R. Hunter, Xavier Leleu, Olivier Tournilhac, Lian Xu, Kelly O'Connor, Robert J. Manning, Daniel Ditzel Santos, Mariana Chemaly, Christopher J. Patterson, Jacob D. Soumerai, Nikhil C. Munshi, Julie A. McEarchern, Che-Leung Law, Iqbal S. Grewal, and Steven P. Treon*
Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, United States
Harvard Medical School, Boston, MA, United States
Jerome Lipper Multiple Myeloma Center, and West Roxbury Veterans Administration Medical Center, Boston, MA, United States
Department of Preclinical Therapeutics, Seattle Genetics, Inc., Bothell, WA, United States
* Corresponding author; email: steven_treon{at}dfci.harvard.edu.
Waldenstrom's macroglobulinemia (WM) is a B-cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow (BM) infiltration with lymphoplasmacytic cells (LPC). Excess mast cells (MC) are commonly present in WM, and provide growth and survival signals to LPC through several TNF family ligands (CD40L, APRIL, BLYS). As part of these studies, we demonstrated that WM LPC secrete soluble CD27 (sCD27), which is elevated in patients with WM (p<0.0009 versus healthy donors), and serves as a faithful marker of disease. Importantly, sCD27 stimulated expression of CD40L on 10/10 and APRIL on 4/10 BM MC samples obtained from WM patients as well as on LAD2 MC. Moreover, the SGN-70 humanized monoclonal antibody which binds to CD70 (the receptor-ligand partner of CD27), abrogated sCD27 mediated upregulation of CD40L and APRIL on WM MC. Lastly, treatment of SCID-hu mice with established WM using the SGN-70 antibody, blocked disease progression in 12/12 mice, whereas disease progressed in all 5 untreated mice. The results of these studies demonstrate a functional role for sCD27 in WM pathogenesis, along with its utility as a surrogate marker of disease and a target in the treatment of WM.
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