In one recent study (Agirre et al 2015, Genome Research) the authors suggest B cell enhancers are inactivated in multiple myeloma. In stem cells/progenitors cells the aforementioned B cell enhancers are inactive and become activated in B cells. Is it known for certain that cancer cells in MM come from transformation of B cells or is it possible that they come from defective stem/progenitor cells?
Myeloma cells have a plasma cell or closely related phenotype. They are also committed to production of a particular immunoglobulin species based on Ig gene rearrangement. However, in some cases the anti-CD20 monoclonal rituximab will reduce paraprotein level despite the malignant cells in marrow being CD20 negative. There are others that know more about malignant plasma cells than I but I think there are reasons to believe that at least in some cases there is evidence for the malignant clone existing at least at the memory B cell stage. However, I am not aware of any evidence for clonal abnormality at earlier stages.
It may be that you are asking a rather complex question that has no one answer. Perhaps the question is at which stage of development does a mutation occur that predestines the cell to become a malignant clone. It is perhaps conceivable that this occurs at the pre or pro B cell stage or even at the stem cell stage but that the malignant clone still goes through maturation stages such as Ig gene rearrangement before expanding to take up bone marrow with a plasma cell phenotype. That would seem pretty unlikely and it might be that clear evidence is available to refute it but it might also be unknowable in practice for any given clone. What might be against it is that as far as I know we do not see malignant clones undergoing several different Ig gene rearrangements, which in theory should perhaps be the case if the cell acquired a malignant propensity at a pre B cell stage, or even at a later stage, considering that there is usually isotype switching to IgG.
The tranlocations responsible for the malignancy are known for a good proportion of myeloma clones. I suspect the people who have published on these would be able to give you a more black and white answer. Everything points to the critical mutation being at least at memory B cell stage I would say, but don't quote me on it.
Dear colleague,
you have asked an essential question in MM genesis, which has nobody answered so far. Most of the experts talk about treatment strategies, which reffer to killing mature plasma cells-I've never found results of differentiation therapy in MM which would be given prior to the maturation of defected or malignant rearanged cells.
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