Mesenchymal stem cells from multiple myeloma patients display distinct genomic profile as compared with those from normal donors

Abstract

It is an open question whether in multiple myeloma (MM) bone marrow stromal cells contain genomic alterations, which may contribute to the pathogenesis of the disease. We conducted an array-based comparative genomic hybridization (array-CGH) analysis to compare the extent of unbalanced genomic alterations in mesenchymal stem cells from 21 myeloma patients (MM-MSCs) and 12 normal donors (ND-MSCs) after in vitro culture expansion. Whereas ND-MSCs were devoid of genomic imbalances, several non-recurrent chromosomal gains and losses (>1 Mb size) were detected in MM-MSCs. Using real-time reverse transcription PCR, we found correlative deregulated expression for five genes encoded in regions for which genomic imbalances were detected using array-CGH. In addition, only MM-MSCs showed a specific pattern of 'hot-spot' regions with discrete (<1 Mb) genomic alterations, some of which were confirmed using fluorescence in situ hybridization (FISH). Within MM-MSC samples, unsupervised cluster analysis did not correlate with particular clinicobiological features of MM patients. We also explored whether cytogenetic abnormalities present in myelomatous plasma cells (PCs) were shared by matching MSCs from the same patients using FISH. All MM-MSCs were cytogenetically normal for the tested genomic alterations. Therefore we cannot support a common progenitor for myeloma PCs and MSCs.

Impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients is associated with a blockade in the deactivation of the Notch signaling pathway

“…Several previous studies indicated that BM-derived MSCs from MM patients showed an enhanced production of cytokines and a distinctive gene expression profile, as compared with their normal counterparts. [1][2][3][4] Although osteoblastic function is decreased in advanced MM, regarding whether and at which level the differentiation of MSCs towards osteoblasts is impaired in this disease, the reports are not unanimous. [1][2][3] In the present study, MSCs from both normal subjects (healthy human donors or naive mice) and MM subjects (MM patients or 5T33MM mice) were used.…”

“…Our data do not allow to conclude whether the impaired osteogenic differentiation of MM-hMSCs is due to an inherent difference, although the genomic profile in ND-hMSCs and MMhMSCs was reported to be much different. 4 We assume that with the persistent stimulation of MM cells in vivo, hMSCs gradually gain abnormalities in gene expression and/or certain signaling pathways of osteoblast differentiation, such as Notch signaling. These abnormalities of MM-hMSCs might still exist in vitro even though MM cells are removed.…”

“…1 Because alemtuzumab as a single agent is more potent than rituximab in CLL, the rationale for this study was to combine this anti-CD52 antibody with a FC chemotherapy backbone. [2][3][4] Mice were given DAPT or dimethyl sulfoxide (DMSO) intraperitoneally 10 mg/kg daily for 20 days (n ¼ 3/group). One leg was used to isolate BM and perform CFU-F assay, and the other leg was used for histomorphometric analysis.…”

Bone osteoblastic and mesenchymal stromal cells lack primarily tumoral features in multiple myeloma patients

“…Accordingly, it has been previously reported that MSCs are cytogenetically normal by FISH analysis, supporting the notion that MM cells and MSCs have no common progenitor. 4 Clearly, our study data should be confirmed in a larger set of patient-derived samples. At present, there are no published studies of isolated OBs in MM patients.…”

“…Alterations of gene expression and genomic profiles have been reported in MSCs of MM patients in comparison with healthy donors as published in Leukemia. 3,4 Moreover, we have recently shown the occurrence of different patterns of gene expression profile, not only in MSCs but also in OBs of MM patients compared with healthy individuals and in relationship to MM bone disease. 5 Nevertheless, it is still unclear whether these bone microenvironment cells in MM patients are primarily tumoral.…”