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Annals of Oncology Advance Access published online on June 20, 2006
Annals of Oncology, doi:10.1093/annonc/mdl109
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© 2006 European Society for Medical Oncology
Received March 30, 2006
Accepted April 11, 2006

original article

Mast cells in Waldenstrom's macroglobulinemia support lymphoplasmacytic cell growth through CD154/CD40 signaling

O. Tournilhac 1, D. D. Santos 1, L. Xu 2, J. Kutok 3, Y.-T. Tai 4, S. Le Gouill 4, L. Catley 4, Z. Hunter 1, A. R. Branagan 1, J. A. Boyce 5, N. Munshi 4, K. C. Anderson 4, and S. P. Treon 1 *

1 Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
2 Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA, USA
3 Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
4 Department of Medicine, Harvard Medical School, Boston, MA, USA; Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, USA
5 Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston MA, USA

* To whom correspondence should be addressed.
S. P. Treon, E-mail: steven_treon{at}dfci.harvard.edu


  Abstract

Bone marrow (BM) mast cells (MC) are commonly found in association with lymphoplasmacytic cells (LPC) in patients with Waldenström's macroglobulinemia (WM). We therefore sought to clarify the role of MC in WM. Co-culture of sublethally irradiated HMC-1 MC, KU812 basophilic cells, or autologous BM MC along with BM LPC from WM patients resulted in MC dose-dependent tumor colony formation and/or proliferation as assessed by 3H-thymidine uptake studies. Furthermore, by immunohistochemistry, multicolor flow cytometry and/or RT-PCR analysis, CD40 ligand (CD154), a potent inducer of B-cell expansion, was expressed on BM MC from 32 of 34 (94%), 11 of 13 (85%), and 7 of 9 (78%) patients, respectively. In contrast, MC from five healthy donors did not express CD154. By multicolor flow cytometry, CD154 was expressed on BM LPC from 35 of 38 (92%) patients and functionality was confirmed by CD154 and CD40 agonistic antibody stimulation, which induced proliferation, support survival and/or pERK phosphorylation of LPC. Moreover, MC induced expansion of LPC from 3 of 5 patients was blocked in a dose dependent manner by use of a CD154 blocking protein. These studies demonstrate that in WM, MC may support tumor cell expansion through constitutive CD154-CD40 signaling and therefore provide the framework for therapeutic targeting of MC and MC-WM cell interactions in WM.

Keywords: mast cells; Waldenstrom's; macroglobulinemia; cd154; cd40; lymphoplasmacytic cells.
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