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.

14th International Myeloma Workshop

Epigenetic reprogramming of bone marrow mesenchymal stem cells in multiple myeloma

Dr Sarah Essex – University of Birmingham, UK


Our work is based on bone marrow stromal cells from myeloma patients, so we’re looking at not the actual cancer cells but the stromal cells which support the cancer cells. In these we’ve grown them out from diseased patients from pre-malignant, so the MGUS patients, and also from controls and we’re comparing these to see if these are helping towards disease progression and survival of the cancer cells.

Why stromal cells particularly?

It’s been shown in other diseases that they’re really important in the progression of disease or, in fact, even in some of the initiation. So we’ve decided to look at that within myeloma, such as rheumatoid arthritis it’s been found to be quite important.

What have you found?

We’ve found that there are genetic differences between control and MGUS and control and myeloma. There are very few differences between the actual pre-malignant and malignant stage, suggesting that it is a change that happens very early on in disease.

And the specifics?

Specifically we’ve found, which I’m talking about tomorrow, is the Wnt pathway. So we’ve found differences across all patients with this, specifically the inhibitors of the Wnt pathway. So that’s where we’ve reached now and we’re now delving into this and seeing what are the specifics within the Wnt pathway and how this might be. So we’ve looked at it from the gene expression point of view but we want to see if this has any functional impact on the actual cells, so that’s where our future research is going now.

What’s the potential?

Two potential new treatments or new targets for treatments within, so not just targeting the cancer cells but targeting the supporting cells as well perhaps, like a double, a two-pronged approach to really break up these niches where these cancer cells survive.

How many patients have you looked at?

With the actual gene arrays that we’ve done we’ve looked at thirty patients, so we’ve looked at ten myeloma, ten MGUS and ten control and that’s basically from a financial point of view - to do each array is about £500 so that’s what we’ve budgeted for. But we have got samples from a lot more patients due to excellent clinical support that we have, so our work around this, we’ve got a lot of patient samples that we can use.

Are you looking at patients from other institutes?

We haven’t so far, they’ve just been from… so I’m based at Birmingham University, so we’ve been looking at local hospitals. But that’s always a potential is to collaborate with other universities and other hospitals to really broaden our patient cohort.

What’s next?

Next, well there’s been some very exciting talks here and pushing us in certain directions but I think we’ll be concentrating on the Wnt pathway that we’re speaking about tomorrow, but also other pathways that have come up on our analysis and really getting the function experiments going because it’s all well and good there being genetic differences but if they don’t translate into functional differences it means nothing in terms of patient treatment. So that’s where we’ll be focussing our aims.