Monday, September 12, 2011

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.


Al Janski said...

References related to Dr. Hamblin's commentary are below.

Al Janski


Stem Cells Central to Pathogenesis of Mature Lymphoid Tumors

"Self-Renewing Hematopoietic Stem Cell Is the
Primary Target in Pathogenesis of Human Chronic
Lymphocytic Leukemia"; Y. Kikushige et al.;
Cancer Cell 20, 246–259, August 16, 2011

"Surprise! HSC Are Aberrant in Chronic
Lymphocytic Leukemia"; Ash A. Alizadeh and
Ravindra Majeti; Cancer Cell 20, August 16, 2011 135-136
"Nearly all current therapies for CLL, including
rituximab, target the mature B cell leukemic
population; however, it may be that therapies
effective at targeting these CLL cells will not
affect the preleukemic HSC. Thus, curative
strategies may need to target not only the
frankly leukemic cells, but also the preleukemic
HSC. How to preferentially target these
preleukemic HSC, as compared to residual normal
HSC, represents a major challenge that will
depend on investigations into the mechanisms that
give rise to these aberrant cells."

Terry Hamblin said...

Yes, I know about the paper. I have been working on a review of it, but I have been a bit weak.

Grateful said...

First, best wishes for your health.

Are you familiar with the work of Dr. Catriona Jamieson at UCSD? I cannot follow all of her work, but from what I do understand it looks like her expertise is with cancer HSCs, and Dr. Kipps worked with her to try to establish a link between CLL and cancer HSCs, but they have not been able to establish such a least not yet.

Luis said...

So CLL stem cell has different markers... How about ALL? will be the same?