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

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.

Clinical and prognostic implications of low or high level of von Willebrand factor in patients with Waldenström macroglobulinemia

“…30 In addition, VEGF expression on bone marrow mast cells was associated with high VWF concentration. Besides growth and survival signals provided to WM LPCs, 31,32 mast cells regulate endothelial cell proliferation and function by means of mediators such as heparin, histamine, and angiogenic factors, especially VEGF. [33][34][35][36][37] Histamine and VEGF have been reported to be involved in VWF exocytosis also.…”

Signaling Pathways in the Activation of Mast Cells Cocultured with Astrocytes and Colocalization of Both Cells in Experimental Allergic Encephalomyelitis

“…Moreover, the interaction between CD40 and CD40L plays an important role in signal transduction pathways in humoral and cell-mediated immune responses. Mast cells may support tumor cell expansion through constitutive CD40-CD40L signaling in Waldenström's macroglobulinemia (29). Blocking CD40-CD40L interactions by anti-CD40L Ab prevents murine or common marmoset EAE disease activity (18,54).…”

“…1C) responses. Mast cells express CD40L, a potent inducer of astrocyte activation (29), and astrocytes functionally express CD40. Cocultures of HMC-1 cells showed higher levels of CD40L and similar levels of CD40, as assessed via Western blot.…”

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

“…68 Mast cells can be observed admixed with the WM B cells in patient BM histology and are thought to play an important supportive role in the tumor microenvironment of WM. 69 Deletions of chromosome 6q were associated with over 131 differentially expressed genes. Levels of previously identified target genes such as the NF-kB negative regulator HIVEP2, as well as BCLAF1, FOXO3 and ARID1B were all suppressed in the presence of 6q deletions.…”