Stromal alterations in patients with monoclonal gammopathy of undetermined significance, smoldering myeloma, and multiple myeloma

Abstract

The hallmark of multiple myeloma (MM) is a clonal plasma cell infiltration in the bone marrow accompanied by myelosuppression and osteolysis. Premalignant stages like monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic stages like smoldering myeloma (SMM) can progress to multiple myeloma (MM). Mesenchymal stromal cells (MSC) are an integral component of the bone marrow microenvironment and play an important role for osteoblast differentiation and hematopoietic support. While stromal alterations have been reported in MM contributing to hematopoietic insufficiency and osteolysis, it is not clear whether alterations in MSC already occur in MGUS or SMM. In this study we analyzed MSC from MGUS, SMM and MM towards their properties and functionality and performed mRNA sequencing to find underlying molecular signatures in different disease stages. A high number of senescent cells and a reduced osteogenic differentiation capacity and hematopoietic support was already present in MGUS MSC. As shown by RNA sequencing there was a broad spectrum of differentially expressed genes including genes of the BMP/TGF-signaling pathway, detected already in MGUS and that clearly increases in SMM and MM patients. Our data may help to block these signaling pathways in the future to hinder progression to multiple myeloma.

Overlapping Stromal Alterations in Myeloid and Lymphoid Neoplasms

“…Previous data from our group and others have indicated that conditioned media from AML cell lines could induce various alterations in MSCs related to growth and differentiation [ 4 , 20 ]. Building upon the hypothesis that soluble factors contribute to stromal alterations, we exposed healthy MSCs to conditioned Media (CM) derived from MNCs of healthy controls and patients with MDS, AML, ALL, and NHL.…”

“…MSCs were cultured as previously described [ 20 ]. MNC fractions were cultured in RPMI + 20% FBS (Sigma Aldrich, St. Louis, MO, USA) and supplemented with IL-3, IL-6, SCF (all 10 ng/mL), and FLT-3Ligand (20 ng/mL), all from Peprotech, Hamburg, Germany, as previously described [ 8 ].…”

“…After 21 days, chondrogenic pellets were cut on a cryostate, and proteoglycane was stained with Safranin O. Alizarin Red staining was used to visualize osteogenic differentiation after 14 days of osteogenic induction in a medium consisting of DMEM low glucose ascorbic acid (50 µg/mL), ß-glycerol-phosphate (10 mM) and dexamethasone (10 −7 M). Differentiation assays were performed as previously published [ 10 , 20 ]. Images were digitalized using SPOT Software version 4.7 (Diagnostic Instruments Inc., Sterling Heights, MI, USA) as previously described [ 10 ] and visualized using an Axiovert 25 microscope (Zeiss, Jena, Germany).…”

Mesenchymal stem cells: paving the way for myeloma onset?

“…In this issue of Blood Advances , in the article entitled “Stromal alterations in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma and multiple myeloma (MM),” Bogun et al 1 performed functional and molecular analyses on bone marrow-derived mesenchymal stem cells (MSCs) isolated from healthy individuals and patients with plasma cell neoplasms at various stages of disease, including MGUS, smoldering multiple myeloma (SMM), and MM. They found that MGUS MSCs already had a high proportion of senescent cells and reduced capacity for osteogenic differentiation and hematopoietic support, which became more pronounced with disease progression.…”