CLL and leukemic stem cells

I have been think about cancer stem cells as they might affect CLL. The concept if that there is a damaged hemopoietic stem cell that feeds in to the tumor that does not carry the same markers as the tumor and would therefore not be susceptible to the type of treatment that would be effective for the bulk of the tumor cells. There is strong evidence that leukemic stem cells exist for acute myeloid leukemia, but the B cell malignancies would seem not to be involved with such because clonal commitment is a late event occurring after rearrangement of the immunoglobulin genes..

However, there is some indirect evidence that a leukemic stem cell might exist. First, there are the familial cases; For these to exist there must be a defect in the germ line - and in at least one family case we know there is a mutation in DAPK. We also know that in families with a high incidence of CLL the CLLs are not clonally related, that there is a 3 times higher incidence of monoclonal B cell lymphocytosis than in normals and that other B cell malignancies also have a higher incidence. Moreover some people finds that MBL is frequently oligoclonal and some people have claimed to find a second B cell clone in up to 10% of patients with CLL. WE, ourselves found that about half of MGUS cases are oligoclonal.

Many years ago (1986) we reported 20 patients with B cell malignancies that had MDS without receiving any form of cytotoxic treatment - evidence that a precursor cell to both myeloid and B-cells was injured. One occasionally sees CLL and CML in the same patient.

Freda Stevenson wrote an important paper in 2010 in Blood which showed that the V1-69 stereotype that is common in CLL was also commonly used in the normal immune response.

So this is how a CLL stem cell would work: a] One would expect that there might be an excess of other hematological malignancies. b] one would expect that there would be an excess of other B cell tumors. c] One would expect that there would be some biclonal or even triclonal CLLs. d] One would expect there to be a precursor condition that was oligoclonal. e] One would expect the same maturation pattern as in the normal immune response.

There is one other fact to add: while MBLs with easily detectable lymphocytoses use the same repertoire of V genes as CLL while those with minimally detectable disease use a random repertoire, the very late relapse of some B cells malignancies.

Having been a sceptic on leukemic stem cells in CLL, my views are changing; all this is only possible if we postulate a very slow progression and a very long natural history.