Saturday, October 13, 2007

Leukemic Stem Cells

The question is often asked as to whether there are leukemic stem cells for CLL. The theory goes like this. Most of the cells in a cancer are committed cells without self-renewal capacity. In any tumor there are small numbers of stem cells carrying the basic neoplastic defect that are capable of self-renewal and differentiation. The great bulk of the cells are differentiated cells that have committed themselves to maturation and eventual death. If you transplanted only those, they would eventually die out because they do not have the capacity for self-renewal. It is suggested that such cells are the ones that are killed by conventional therapy, while the true stem cells are resistant to treatment. This explains the phenomenon of remission and relapse. The great bulk of cells of the tumor are not stem cells so that when they respond to treatment the patient appears to be in complete remission. However, lurking somewhere in the body are the stem cells that are resistant to the treatment, and when the coast is clear they will start dividing and replenish all the cells that have been killed so that the disease relapses.

This scenario certainly appears to be the case for many solid tumors like colon cancer and pancreatic cancer, and is also the case for myeloid leukemias, both acute and chronic. Is it also the case for lymphoid tumors, and especially for CLL?

I submit that it cannot be so. The stem cells of lymphocytes are pluripotent blasts found in the bone marrow, that can commit to either myeloid or lymphoid tumors. That is why in chronic myeloid leukemia, transformation can be to either acute myeloid leukemia or acute lymphoid leukemia. However, lymphoid tumors mostly arise from lymphocytes that have already committed themselves by rearranging their immunoglobulin genes (in the case of B cells tumors) or their T cell receptor genes (in the case of T cell tumors). This is a step that can't be gone back on. You can certainly conceive of a stem cell origin for a lymphoid tumor, but there is no reason that all the cells in such a tumor would have the same Ig rearrangement in every cell as happens in CLL, myeloma and mantle cell lymphoma, and while where there is some variation in follicular lymphoma, it is usually possible to construct a 'family tree' of the variations demonstrating an origin in a single cell.

If relapse in CLL was fed by a self-renewing stem cell from a lineage arising before Ig rearrangement the relapsing tumor would have a different rearrangement.

In fact lymphocytes have a circular lifestyle. The apparently small mature lymphocytes of CLL can turn back into blasts capable of division before resuming their 'mature' appearance again. there is no need for a stem cell to answer the relapse/remission conundrum. There may certainly be cells that lack Cd20 and are thus immune to rituximab, but they are not stem cells in the conventional way.


Anonymous said...

I wasn't aware that the question if CLL arises from leukemic stem cells was often asked. It's a recent thought, I'd submit, because of the finding that not all breast cancer cells will give rise to tumors; those that do apparently are different than those that do not.

The question you raise is an interesting one.

Certainly in CLL there are what one might call progenitor cells. It does seem curious that conventional karyotyping is not often done in CLL because the cells are not seen to often divide. They seem to be arrested in the G0 phase, and are not actively dividing.

Your theory may be correct. Perhaps you could provide a paper or two that supports this idea. My understanding is that the lymphoblasts differentiate into plasma cells, which produce antibodies. I was unaware of the ability of lymphoblasts to differentiate backwards, so to speak, into mature B lymphocytes.

Terry Hamblin said...

Cancer stem cells are a big thing at the moment and the subject of many grant proposals. I have seen a couple looking at a variety of lymphoid tumors.

Cells leaving the germinal center can either differentiate into plasma cells and make antibody, or become memory cells. Memory cells circulate and when they meet antigen can go through the whole division/proliferation cycle again. They do this in tissue not in the blood. In CLL they do it in proliferation centers, assuming the morphology of lymphoblasts. Although PB cells in CLL are mainly in G0 they can be made to divide with appropriate mitogens. It is perfectly possible to do cytogenetics in this way. There is a huge literature out there about the life cycle of B lymphocytes. It would take be a little while to dig it out though.

Barry Lambert said...

Doesn't the fact that the lymphocytes generally keep increasing as CLL progresses mean that the tumerous ones are actively dividing (albeit at a low rate)?

Grateful said...

UCSD had a symposium last year,and Dr. Catriona Jamieson had a presentation on this topic. It was mostly about CML and non-CLL, so I don't remember much about it.

Anonymous said...

I did not mention memory cells as those do not enter into the discussion. Of course you are correct.

If antigen stimulation is at least part of the picture as to what is driving the clonal expansion, the question that remains unanswered...what antigen?

One often encounters the notion that constant antigen stimulation may be driving CLL clonal expansion. There is evidence that Terry is well aware of.

I am still of the opinion that the proliferating CLL cells are unlike the cells one finds in the blood, in particular. If the proliferating center is the lymph node, as seems likely, then the standard expansion of a defective clone may be at play.

Barry's question is answered by saying, yes, the increase in numbers of CLL cells is due to an unequal balance between proliferation and apoptosis, in the favor of proliferation.

Barry Lambert said...

If there is an antigen that causes CLL cells to increase, it seems it must be one that healthy lymphocytes cannot recognize and that stays in the body continously. At least early in the disease, there is still a population of such healthy lymphocytes providing undiminished immune protection and yet the clonal expansion seems to progress fairly steadily (at least that is my own experience so far).

Terry Hamblin said...

What is the nature of the antigen? Some people believe that it is an autoantigen - unmutated IgM does recognise certain self antigens. V4-34 recognises a superantigen on red cells even when mutated. Although there are remnants of the normal B cell repertoire left, they don't finction normally.