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Keywords | Multiple myeloma | cancer stem cell | clonal disease progression |<br />
MSCNET<br />
Myeloma Stem Cell Network:<br />
a translational programme identifying<br />
and targeting the myeloma stem cell<br />
Summary<br />
Multiple myeloma (MM) is a disease where malignant plasma<br />
cells accumulate in the bone marrow. Normal plasma<br />
cell development at this site is thought to refl ect a synchronous<br />
terminal diff erentiation of B cells that have followed<br />
sequential stages of maturation. In MM, however, disease<br />
characterisation has revealed a number of phenotypic and<br />
molecular features that suggest the existence of a clonally<br />
related ‘less mature’ cell, and the question arises whether<br />
this may be a stem cell critical to propagating disease.<br />
To address this, the MSCNET has formulated a strategy<br />
which includes genomic and proteomic approaches, in<br />
order to examine the nature of the cell underlying MM disease<br />
origins and progression. This will utilise both in vitro<br />
and in vivo models of the disease, and examine MM at presentation<br />
and during its advance, in order to track factors<br />
governing disease behaviour in this regard.<br />
Problem<br />
MM is at present an incurable disease, for which eff ective<br />
new therapies are being actively sought. It is by no means<br />
clear, however, what the nature of clonal propagation is in<br />
MM. To progress work in this area, the MSCNET has set out<br />
to identify the nature of the cell underlying disease survival<br />
and persistence.<br />
One of the most striking concepts emerging in cancer biology<br />
is a role for cancer stem cells (CSCs) in feeding malignant<br />
cell growth and tumour maintenance. By defi nition, these<br />
CSCs have an indefi nite self-renewal potential, and are able<br />
to populate both their own pool and the growth of the<br />
tumour. Although the fi rst indication that such a cell might<br />
exist came from studies in leukaemia, evidence for CSCs<br />
in solid tumours lends further support for the concept of<br />
a myeloma stem cell. The question for the MSCNET is whether<br />
such a stem cell exists in MM.<br />
BIOLOGY<br />
Aim<br />
Based on the above hypothesis, the aims will be:<br />
• to study whether the putative myeloma stem cell (MSC)<br />
exists as a less diff erentiated clonally related memory<br />
B-cell or as a more mature plasma blast/plasma clonogenic<br />
cell;<br />
• to identify genes of potential impact on stem cell function;<br />
• to propose new therapeutic strategies.<br />
Expected results<br />
The results of the scientifi c programme are expected to<br />
redefi ne stem cell characteristics and especially to characterize<br />
the myeloma stem cell compartment and its progeny,<br />
as well as its relationship to the tumour micro-environment.<br />
This insight will allow us to examine whether there are any<br />
MSC-related features that can be targeted by future specifi c<br />
therapies to ablate malignant disease.<br />
Potential applications<br />
Identifying the nature of the MSC will have a profound<br />
impact on our understanding of pathogenesis, not only for<br />
MM but for all malignant B-cell diseases. Importantly, the<br />
MSCNET is well placed to identify potential drug-based<br />
approaches to attack MSC and disease progression.<br />
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