Decreased affinity of rhTRAIL-D269H/E195R to OPG overcomes TRAIL-resistance mediated by the bone microenvironment [Cell Biology]

November 26th, 2013 by Bosman, M. C. J., Reis, C. R., Schuringa, J. J., Vellenga, E., Quax, W. J.

The bone marrow microenvironment provides important signals for the survival and proliferation of hematopoietic and malignant cells. In multiple myeloma (MM), plasma cells are surrounded by stromal cells including osteoblasts. These stromal cells protect MM cells from apoptosis induced by chemotherapeutic agents. Osteoprotegerin (OPG), a soluble receptor of the cytokine TNF-related apoptosis-inducing-ligand (TRAIL), is secreted by osteoblasts and has been implicated in the prevention of cell death induced by TRAIL in malignant cells. Previously, we have designed death receptor-specific TRAIL variants, which induce apoptosis exclusively via one of its death receptors. Here, we have studied in detail the interaction between rhTRAIL variants and OPG. We show that a DR5-specific variant (rhTRAIL D269H/E195R) displays a significantly decreased affinity to OPG. Furthermore, this rhTRAIL variant shows a much higher activity compared to rhTRAIL WT, and retains its effectiveness in inducing cell death in multiple myeloma cell lines, in the presence of OPG secreted by stromal cells. We also demonstrate that stromal cells are largely insensitive to high concentrations of this rhTRAIL variant. In conclusion, rhTRAIL D269H/E195R is a potential therapy for multiple myeloma due to its high effectiveness and diminished binding to OPG.