Epigenetic reprogramming of bone marrow mesenchymal stem cells in multiple myeloma

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Published: 5 Apr 2013
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Dr Sarah Essex - University of Birmingham, UK

Dr Essex talks to ecancertv at the 14th International Myleoma Workshop (IMW 2013), Kyoto, Japan, 3-7th April 2013.

Multiple myeloma (MM) plasma cells co-cultured with stroma taken from MM bone marrow demonstrates that it is the stroma, rather than the plasma cell, that acts as a major determinant of disease progression in MM. The role of bone marrow mesenchymal stem cells (BMMSC) in the progression of MM and monoclonal gammopathy of undetermined significance (MGUS) was investigated.

BMMSC were isolated from control, MGUS and MM bone marrow. The full genetic profile of these cells was examined using microarrays, with detailed pathway analysis to determine the genes involved in disease progression. 30 patients BMMSC were analysed using U133 plus 2.0 GeneChip microarrays; this highlighted 187 genes that had over a 1.5 fold difference in expression between control and disease BMMSC. Pathway analysis of these genes generated several differentially expressed pathways, with Wnt signalling being the most evident. Two Wnt pathway genes whose expression is significantly decreased in disease BMMSC are secreted frizzled-related proteins (sFRPs) 2 and 4.

This decrease in expression was confirmed by RT-PCR, with a concurrent increase in methylation status suggesting these genes have become epigenetically silenced. Splice variant analysis of these particular genes showed a differential expression of exons, which may be functionally significant for Wnt signalling. For the first time Dr Essex's team showed profound silencing of negative regulators of Wnt signalling within MM and MGUS BMMSC, which may help to design early interventions aimed at patients in the premalignant state.