Purpose: Mesenchymal stem cells (MSCs) are an essential component of the bone marrow (BM) microenvironment and have shown to support cancer evolution in multiple myeloma (MM). Despite the increasing evidence that MM MSCs differ from their healthy counterparts, little knowledge exists as to whether MSCs independently influence disease outcome. The aim of the present study was to determine the importance of MSCs in disease progression and outcome in MM. Experimental Design: To determine the impact of MSCs on MM outcome in an in vivo system, we first identified genes from cultured MSCs that were specific to MSC expression and were not or minimally expressed in PCs or other cells present in BM aspirates. We then applied this MSC gene signature to whole BM biopsies of MM patients compared to healthy controls and determined MSC expression scores specific to MM and predictive of outcome. Results: We show that MM MSC gene expression signatures are able to differentiate MM from monoclonal gammopathy (MGUS) and smoldering MM (SMM) as well as from healthy controls and treated MM patients that have achieved a complete remission (CR). We identified a prognostic gene score based on three MSC specific genes COL4A1, NPR3 and ITGBL1, that was able to predict progression free survival (PFS) in MM patients and progression into MM from SMM. Conclusions: Our findings show that progression of MM and of SMM into MM not solely relies on intrinsic PC factors, but is independently impacted by the biology of the surrounding microenvironment.
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