Fogd_EU Haematology 03/03/2010 13:20 Page 95
The Cancer Stem Cell Concept in Multiple Myeloma – From Phenomenology to Characterisation
Insights from Normal B-cell Development Figure 1: Possible Multiple Myeloma Cancer Stem
There are four biological hallmarks of normal B-cell development:
Cell Compartments
rearrangement of the heavy chain;
Clonotypic memory
B cell
rearrangement of the light chain;
somatic hypermutation; and
class switching.
The initial rearrangement of the heavy and light chains is characteristic
of pre-B cells and B cells, respectively, and takes place in the bone
Clonotypic Clonotypic Malignant
Germinal centre B cell plasmablast plasma cell
marrow as part of early B-cell development. However, somatic
hypermutation and class switching take place in the germinal
centre of the lymph node after antigen recognition.
7
Interestingly,
rearrangement of the immunoglobulin light and heavy chains as well Lymph node
as somatic hypermutation can be found in the malignant plasma
There are two possible routes in the germinal centre of the lymph node that could lead to
cells.
8–10
This indicates that the malignant plasma cells in MM have
the malignant plasma cell clone. In the first, the multiple myeloma cancer stem cell
undergone normal B-cell development and are exposed to the same
+
(MMCSC) is present in the CD19 post-germinal clonotypic B-cell compartment with heavy
chain rearrangement and somatic hypermutation. This would include memory B cells and/or
biological control as their normal counterparts, and that the malignant
plasmablasts. In the second, the MMCSC is a more mature cell type that is present within
plasma cell is derived from a post-germinal B-cell type. We believe that
the malignant plasma cell population itself.
there are two possibilities: the MMCSC will be found either in the
malignant plasma cell compartment itself or in an earlier B-cell CD138
+
cells. Furthermore, the results indicated that the colony-
differentiation step (see Figure 1). forming CD138
-
cells were positive for CD19, CD45 and CD22. In
line with these results, Billadeau et al.
9
found clonotypic B-cells in
Evidence for the Presence of a the CD38
-
/CD45
+
population with pre-switched immunoglobulins
Multiple Myeloma Cancer Stem Cell IgA and IgM.
Two characteristics describe the CSC: self-renewal and differentiation
to tumour cells. An early study by Hamburger and Salmon
11
showed Although the clinical significance of the presence of clonotypic CD19
+
that cells from bone marrow aspirates from myeloma patients cells is unknown, it is worth noting that these clonotypic cells are
were able to form colonies in vitro displaying the phenotypic traits present in the peripheral blood of patients after systemic therapy
of plasma cells.
11
Furthermore, clonogenic growth occurred at a (reviewed in reference 12). Therefore, it would be interesting to look
frequency of one in 100–100,000 cells.
12
Colonies were established further into subpopulations of the CD19
+
cells from the peripheral
from 86% of the patient samples and the majority of these cells blood of MM patients, as it might be possible to identify a stem cell
contained monoclonal immunoglobulin in the cytoplasm that was candidate here.
identical to the type found in the patient’s serum or urine.
11
Similar
findings were reported in a later study by Matsui et al.
13
It is Direct evidence for the presence of an MMCSC is still missing, as
therefore likely that cells capable of self-renewal and experiments showing self-renewal as well as tumour-regeneration
differentiation are present in MM. However, a candidate CSC still capacity of a cell type with well-defined markers is still lacking. This
remains to be identified based on surface markers, as was the would require experiments similar to those described for AML.
case for AML. However, based on knowledge from previous published studies,
the odds are in favour of being able to identify an MMCSC within
As mentioned above, there is some evidence that a CSC in MM should the CD19
+
fraction of the peripheral blood. Consequently, a
be isolated from an earlier B-cell stage than the plasma cell, as European consortium of scientists called the Myeloma Stem Cell
so-called clonotypic B-cells have been identified in the peripheral Network (MSCNET) was established in November 2006 as a
blood of MM patients that have the same rearrangement of the translational programme to identify and target the myeloma stem
immunoglobulin heavy chain as the malignant plasma cells.
14–18
cell. The network is supported by the EU’s Sixth Framework
Programme and has formulated a strategy that includes genomic
A few groups have looked into additional markers. Rasmussen et and proteomic approaches to examine the nature of the cell
al.
18
suggested that a clonal hierarchy was present in MM. underlying MM disease origins and progression.
In peripheral blood, they identified three clonotypic subpopulations
from ‘immature’ CD19
+
/CD38
-
, expressing immunoglobulin G Perspectives
(IgG) or IgA, to more mature populations of CD19
+
/CD38
+
and If the hypothesis of an MMCSC is accepted, two main considerations
CD19
+
/CD38
++
expressing IgA only – all with expression of the in patient treatment are evident. First, with the use of autologous
initial translocations and oncogene activation. Furthermore, transplants there is a high risk of infusing the MMCSC to the patient;
clonotypic memory B cells were found in the peripheral blood of therefore, methods should be developed that remove the CSC from
70% of the patients post-transplantation, with a frequency of 0.1% the transplant.
20
Second, a new therapy should be developed
in the memory B-cell population.
19
that not only eliminates the malignant plasma cells that cause
the symptoms but also targets the MMCSC populations.
21
Finally, the
In another line of investigation, Matsui et al.
13
divided patient presence or absence of the MMCSC after treatment might be a new
samples into CD138
-
or CD138
+
cells. The CD138
-
cells were found tool in evaluating the effect of a treatment, as well as redefining
to have colony-forming potential and to be able to differentiate into remission and the prognosis of the patient. n
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