Biomedical Engineering Reference
In-Depth Information
that CD96 is present on the majority of AML LSC and may be useful in
developing LSC-specific therapy in the future.
Thus, it is now believed that the LSC is derived from an HSC following one
or more leukemogenic events (Fig. 2). These cells, also called SL-IC, make up a
very small proportion of the total leukemic cell population (0.2-1%). Chronic
myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) have also
been described as HSC disorders (Eaves et al. 1998; Cobaleda et al. 2000).
Leukemogenic
event(s)
Self-renewal
Self-renewal
HSC
LSC
Clonogenic
leukemia cells
Non-clonogenic
leukemia blast cells
Fig. 2 Schematic diagram of the transformation of an HSC to a LSC which also retains
the capacity to self-renew. Following a number of intermediate progenitor stages, the leuke-
mic blast cells are produced and these blast cells form the vast majority of leukemic cells
present
CML is a clonal myeloproliferative disorder which develops when a single,
multipotent HSC acquires the Philadelphia (Ph) chromosome, which is an
abnormal, shortened chromosome 22 that results from a reciprocal transloca-
tion between the long arms of chromosomes 9 and 22 and is designated
t(9;22)(q34;q11) (Rowley 1973). In the 1980s, it was shown that this transloca-
tion resulted in the ABL proto-oncogene, normally on chromosome 9, becom-
ing juxtaposed with the breakpoint cluster region (BCR) on chromosome 22
(Bartram et al. 1983; Groffen et al. 1984), resulting in production of the unique
fusion gene product BCR-ABL, a 210 kD oncoprotein, often referred to as
p210
BCR-ABL
, which is a constitutively active tyrosine kinase (Lugo et al. 1990)
and results in increased proliferation, abnormal cell adhesion, and reduced
apoptosis of the malignant clone.
CML progresses through three phases, the first is chronic phase which is
associated with expansion of the granulocyte series with the cells retaining the
capacity to differentiate. In the next phase, accelerated phase, there is the
development of additional cytogenetic abnormalities and increased numbers
of more primitive cells in the peripheral blood. The final phase, blast crisis, is
characterized by the expansion of myeloid or lymphoid blasts, with loss of the
ability of these cells to differentiate, and this final phase behaves like an acute
