Biomedical Engineering Reference
In-Depth Information
exclusively into two prognostic subsets based on the mutational status of
immunoglobulin variable heavy chain (V
H
) genes (Damle et al. 1999; Hamblin
et al. 1999), it was suggested that there may be two distinct cells of origin for
CLL: one derived from pre-germinal center (GC) naı
¨
ve B cells carrying unmu-
tated V
H
genes (unmutated CLL), the other derived from post-GC memory B
cells carrying mutated V
H
genes (mutated CLL) (Stevenson and Caligaris-
Cappio 2004). However, gene expression profiles of unmutated and mutated
CLL have been shown to be broadly similar both to each other and to antigen-
experienced memory B cells (Klein et al. 2001). These studies therefore strongly
suggest that the CLL cell of origin is a memory B cell. However, a small study of
peripheral blood samples taken from CLL patients revealed the presence of a
CD19
+
CD5
+
population of cells that efflux Hoechst 33342, thus exhibiting
the 'side-population' phenotype characteristic of stem cells (Foster et al. 2006).
This side-population was not identified in normal healthy donors and identifies
a putative stem cell population within CLL. Recent work from our own
laboratory has generated a mouse CLL-like model system, by expressing a
plasmid-encoding dominant-negative protein kinase Ca (PKCa-KR) in HSCs
derived from wild-type mice and then culturing these cells in B-cell generation
systems in vitro and in vivo. This resulted in the formation of a population of
cells that bear hallmark characteristics of human CLL cells with the phenotype
CD19
hi
CD5
+
CD23
+
IgM
lo
, arrest at G
0
/G
1
phase of the cell cycle ex vivo,
and resistance to apoptosis (Nakagawa et al. 2006; Michie and Nakagawa,
unpublished observations). Moreover, PKCa-KR-expressing HSCs possessed
an enhanced proliferative capacity both in vivo and in vitro, potentially reflect-
ing the dynamic cellular kinetics that exist during the progression of human
CLL (Messmer et al. 2005). Clearly further studies are required to determine
whether CLL can be considered a stem cell-mediated disease.
3 Committed Progenitor Cells as Candidate LSCs
The studies described above for AML, CML, and ALL show that, depending
on the type of leukemia and its stage or subtype, the candidate LSC may be an
HSC or a more committed progenitor which has acquired the potential to self-
renew. In addition to identification of the granulocyte-macrophage progenitor
as the candidate LSC in blast crisis CML (Jamieson et al. 2004), the acquisition
of self-renewal potential by committed progenitor cells has been confirmed in
two murine models of AML (Cozzio et al. 2003; Huntly et al. 2004). These
important studies showed that transduction with either the MOZ-TIF2 or
MLL-ENL oncogene resulted in the development of the capacity for self-
renewal in purified populations of committed non-self-renewing myeloid
progenitors in vitro and rapid induction of leukemia in murine serial transplanta-
tion models. Both MOZ-TIF2 and MLL-ENL were cloned from human leuke-
mias and are capable of producing leukemias in murine models. Interestingly, the
