Stem Cells in Leukemia and Other Hematological Malignancies - Stem Cells and Cancer - page 120

of IL-3 expression and entry of cells into a continuously cycling state
(Holyoake et al. 2001). The phenomenon of quiescence in LSC is important
because it would be predicted that the growth factor-independent quiescent
LSC would have a proliferative advantage over normal quiescent HSCs when
the concentration of cytokines is low.
2.2 Acute Lymphoblastic Leukemia
Cobaleda et al. demonstrated that, in NOD-SCID mice, the SL-IC capable of
inducing human Ph + ALL possessed the differentiation and self-renewal capa-
city of a candidate LSC (Cobaleda et al. 2000). In these studies, the SL-ICs from
all animals analyzed were exclusively CD34 + CD38 , with a similar cell surface
phenotype to SRC, indicating that an HSC and not a committed progenitor is
the target for leukemic transformation in Ph + ALL. However, the true identity
of the LSC in ALL has been controversial. Cox et al., again using a NOD-SCID
model, demonstrated that cells with a more immature phenotype (CD34 +
CD10 CD19 ), rather than committed B-lymphoid progenitors were the
most likely candidate LSCs for transformation to B-ALL (Cox et al. 2004). In
addition, this study provided evidence for a hierarchical organization of ALL
progenitors as the majority of CD45 + cells harvested from the NOD-SCID
bone marrow were CD34 + , CD10 + , CD19 + , and CD22 + , indicating that
CD34 + CD10 and CD34 + CD19 subpopulations of B-ALL cells underwent
a degree of differentiation in vivo. Contrary to this, other studies have identified
the ALL-propagating cells as CD19 + . Castor et al. demonstrated that while in
p210 Ph + ALL the candidate LSC was an HSC, in other subtypes of ALL (p190
Ph + ALL and TEL-AML1 fusion) the cell targeted for subsequent leukemic
transformation was a committed B-cell progenitor (Castor et al. 2005). Very
recently, Hong et al. have studied a monochorionic twin pair with the TEL-
AML1 fusion, one with frank leukemia and one in the pre-leukemic phase
(Hong et al. 2008). This important research using primary human material
has shown that a CD34 + CD38 /lo CD19 + cell is the candidate LSC and that
the TEL-AML1 fusion acts as a first-hit mutation by endowing the pre-leukemic
TEL-AML1 + cells with altered survival and self-renewal properties.
2.3 Candidate LSCs in Chronic Lymphoproliferative Disorders
Chronic lymphoproliferative disorders, including plasma cell dyscrasias, are
considered to arise from the transformation of lineage-committed lymphocyte
populations, therefore the leukemia-initiating cell in these cases is not consid-
ered to have stem cell-like properties. The same is considered to be true in the
case of chronic lymphocytic leukemia (CLL), although the cell of origin for
CLL has not been formally identified. Indeed, as CLL can be divided almost