Imprinting of Mesenchymal Stromal Cell Transcriptome Persists even after Treatment in Patients with Multiple Myeloma

Abstract

Introduction. Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal expansion of malignant plasma cells (MM cells) in the bone-marrow (BM) compartment. BM mesenchymal stromal cells (MSC) from newly diagnosed MM patients were shown to be involved in MM pathogenesis and chemoresistance. The patients displayed a distinct transcriptome and were functionally different from healthy donors’ (HD) MSC. Our aim was to determine whether MM–MSC also contributed to relapse. Methods. We obtained and characterized patients’ MSC samples at diagnosis, two years after intensive treatment, without relapse and at relapse. Results. Transcriptomic analysis revealed differences in gene expression between HD and MM-MSC, whatever the stage of the disease. An easier differentiation towards adipogenesis at the expense of osteoblatogeneis was observed, even in patients displaying a complete response to treatment. Although their transcriptome was similar, we found that MSC from relapsed patients had an increased immunosuppressive ability, compared to those from patients in remission. Conclusion. We demonstrated that imprinting of MSC transcriptome demonstrated at diagnosis of MM, persisted even after the apparent disappearance of MM cells induced by treatment, suggesting the maintenance of a local context favorable to relapse.

Characterization of the biological and transcriptomic landscapes of bone marrow-derived mesenchymal stem cells in patients with multiple myeloma

“…Notably, due to the pivotal role in the hematopoietic microenvironment and dual immunomodulatory capacity, more and more literatures have emerged to elucidate the potential pathogenesis of MSCs in a variety of disorders such as aplastic anemia [18], acute myelogenous leukemia [17], and type 2 diabetes mellitus [20]. For instance, Spelat et al and Lemaitre L et al respectively suggested the involvement of the cytokines (e.g., IL-6, IL-10) in secretome and transcriptome for MM development via facilitating MM cell proliferation [38,39]. As to MM, talented pioneers in the field have also indicated the diverse abnormalities in the cellular phenotype and distinct genomic profile to a certain extent [40][41][42][43][44].…”

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

“…Furthermore, SSPC gene expression is largely altered by MM, as demonstrated by in vitro co-culture studies of SSPCs with MM cell lines [114,115]. Even after ex vivo expansion of SSPCs without MM cells, the gene expression profiles of SSPCs from patients with MM are distinguishable from SSPCs from patients with premalignant monoclonal gammopathy of undetermined significance (MGUS; an asymptomatic condition that precedes MM) and healthy donors [114,[116][117][118][119]. Deregulated transcriptional pathways include cell cycle regulation, osteoblast maturation, MM cell survival factors, and immune-modulating factors [117,119].…”

“…Deregulated transcriptional pathways include cell cycle regulation, osteoblast maturation, MM cell survival factors, and immune-modulating factors [117,119]. The deregulation of gene expression in SSPCs persists after anti-myeloma therapy [113,118,119], even in patients who are negative for measurable residual disease [119], suggesting a permanent modulation of the cells. This is supported by findings of genomic alterations [120] and epigenetic modifications of the SSPC genomes in MM, dependent on disease stage and inducible by MM cell co-culture [121].…”

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers

“…In detail, Schinke et al identified a prognostic MSC three-gene score, including collagen type IV alpha 1 (COL4A1), natriuretic peptide receptor 3 (NPR3), and integrin beta like 1 (ITGBL1), which is able to predict progression-free survival in MM patients and the progression of MGUS/SMM to MM [161]. Of note, as MSCs from patients who underwent completed treatment show a transcriptome essentially identical to that of patients at diagnosis, persistent printing could maintain a niche prone to relapse [163]. Single-cell sequencing also confirmed that current antitumor therapy fails to counteract MSC inflammation, highlighting their role in disease persistence [164].…”

“…As the immunological dysfunction of MSCs was observed already in SMM stromal cells but not in MGUS ones, the activation of an MSC-induced immunosuppressive microenvironment might contribute to the transition from MGUS to MM as an evolutionary advantage acquired during the multistep development of MM. Of note, MSCs from relapsed patients have an increased immunosuppressive ability compared to those from patients in remission [163]. The support of malignant clone proliferation by MM-MSCs is mediated by the stromal activation of the PD1/PDL-1 axis, disrupting T cell immune response [171,172].…”