Biomedical Engineering Reference
In-Depth Information
leukemia. Interestingly, the Ph chromosome is also found in
20% of de novo
adult ALL and
<
5% of pediatric ALL and, if present, carries a very poor
prognosis (Wong and Witte 2004). The first evidence for the presence of LSC in
CML came in 1998 when Wang et al. demonstrated that sublethally irradiated
NOD-SCID mice, intravenously injected with peripheral blood or bone mar-
row fromCML patients, had persistence of normal and leukemic human cells in
bone marrow for up to 7 months (Wang et al. 1998). Additional research has
shown that, in CML, BCR-ABL can be detected in myeloid, megakaryocytic,
erythroid, and B-lymphoid lineages, accounting for the transformation to an
acute myeloid or lymphoid leukemia when the disease progresses into blast
crisis (Fialkow et al. 1977; Martin et al. 1980). This provides further evidence
for the candidate LSC in CML being an HSC. However, a more recent study by
Jamieson et al. indicates that, in blast crisis CML, granulocyte-macrophage
progenitors acquire the potential for self-renewal through activation of
b-catenin (Jamieson et al. 2004). This acquisition of stem cell characteristics
by a more mature progenitor population is postulated to be responsible for the
transformation of CML from chronic or accelerated phase to blast crisis.
The identification of LSC in myeloid leukemias has served as an important
model system for advancing the study of cancer development in both leukemias
and solid tumors. At present, the hypothesis for the development of myeloid
leukemias is that the less aggressive myelodysplastic syndromes (MDS) and
myeloproliferative disorders progressively evolve into acute leukemias which
are rapidly fatal if left untreated. Numerous different cytogenetic abnormalities
have been described in association with myeloid leukemias (McCormack et al.
2008), with specific abnormalities being associated with specific subtypes of
leukemia with different laboratory and clinical features.
In most leukemias, although the blast cell population is morphologically
homogenous, the leukemic cells are functionally heterogeneous. At any time,
like HSC, the majority of LSC are quiescent (in G
0
). This was first demon-
strated in a SCID murine model in which mice transplanted with primary
leukemia cells had residual leukemia following treatment with the cell cycle-
specific agent 5-fluorouracil (Terpstra et al. 1996). CML is incurable using
repeated AML-type chemotherapy (Kantarjian et al. 1991) suggesting that
there is a pool of quiescent CML stem cells which are resistant to treatment.
Studies have now confirmed the existence of a highly quiescent population of
LSC in CML (Holyoake et al. 1999a). In this study by Holyoake et al., viable
BCR-ABL
+
G
0
cells were isolated using Hoescht 33342 and Pyronin Y stain-
ing from total CD34
+
CML cells by FACS and were demonstrated to have in
vitro progenitor activity by LTC-IC assay and the capability of engrafting
immunodeficient mice. The ability of these quiescent CML stem cells to
produce leukemic progeny also illustrates the reversibility of this quiescent
state. Further research showed that the entry of BCR-ABL
+
progenitors into
a quiescent state in vivo was greatest in the most primitive leukemia cell
populations. This was associated with downregulation of IL-3 and G-CSF
gene expression, and spontaneously reversed in association with upregulation
