Abstract
Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma, but the pathophysiologic effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in hematologic malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent multiple myeloma cells including primary multiple myeloma cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent multiple myeloma cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and extracellular signal-regulated kinase 1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 patients with multiple myeloma and found that it correlated with disease prognosis. Specifically, patients with high levels of pGDF15 had lower probabilities of event-free and overall survival 30 months after diagnosis than patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for multiple myeloma cells, which is pathophysiologically linked to both initial parameters of the disease as well as patient survival.
Highlights
Multiple myeloma is a clonal plasma cell malignant disease that accounts for 13% of hematologic cancers [1]
We first measured the survival of a stroma-dependent (MOLP-6) and a stroma-independent (MM1.S) multiple myeloma cell lines and primary multiple myeloma cells under serum-free conditions supplemented with titrated concentrations of growth differentiation factor 15 (GDF15)
GDF15 increased the MOLP-6 cell and the primary multiple myeloma cells survival: 200 ng/mL of GDF15 yielded up to 70.3% Æ 5.6% viable MOLP-6 cells (P < 0.005) and 74.0% Æ 5.9% viable primary multiple www.aacrjournals.org
Summary
Multiple myeloma is a clonal plasma cell malignant disease that accounts for 13% of hematologic cancers [1]. Prognostic factors reflecting tumor burden, tumor damage in organs and tissues, and intrinsic characteristics including genetic abnormalities have been described, but so far, none of these reflect the multiple myeloma microenvironment [5,6,7,8,9,10,11,12]. Multiple myeloma has been a prototypic disease model for the study of interactions between the microenvironment and malignant cells [13] and has led to the development of novel drugs such as immunomodulatory drugs and proteasome inhibitors, which target multiple myeloma cells and their microenvironment [14]. A better understanding of the mechanism by which the multiple myeloma microenvironment affects the disease is still required to define new therapeutic targets
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