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

• Published in: Annals of oncology Vol. 17; no. 8; pp. 1275 - 1282
• Main Authors: Tournilhac, O., Santos, D. D., Xu, L., Kutok, J., Tai, Y.-T., Le Gouill, S., Catley, L., Hunter, Z., Branagan, A. R., Boyce, J. A., Munshi, N., Anderson, K. C., Treon, S. P.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.2006; Oxford Publishing Limited (England)
• Subjects: Antineoplastic agents; B-Lymphocytes - chemistry; B-Lymphocytes - pathology; Biological and medical sciences; Bone Marrow Cells - chemistry; Bone Marrow Cells - pathology; cd154; cd40; CD40 Ligand - analysis; CD40 Ligand - antagonists & inhibitors; CD40 Ligand - metabolism; Cell Proliferation - drug effects; Coculture Techniques; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; lymphoplasmacytic cells; macroglobulinemia; mast cells; Mast Cells - chemistry; Mast Cells - drug effects; Mast Cells - pathology; Medical sciences; Pharmacology. Drug treatments; Recombinant Fusion Proteins - pharmacology; Signal Transduction; Tumor Cells, Cultured; Waldenstrom Macroglobulinemia - metabolism; Waldenstrom Macroglobulinemia - pathology; Waldenstrom's; Cell proliferation; Immunopathology; Malignant hemopathy; Waldenstrom's; mast cells; In vitro; cd154; Signal transduction; cd40; Immunoglobulinopathy; Lymphoproliferative syndrome; CD40 ligand; Mast cell; macroglobulinemia; Waldenstrom macroglobulinemia; lymphoplasmacytic cells
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdl109

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.