Biomedical Engineering Reference
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achieved a complete molecular response (BCR-ABL negative by RT-PCR),
the number of BCR-ABL transcripts rapidly increased over the following
3 months to at least pre-treatment levels (Cortes et al. 2004; Mauro et al.
2004). This indicates that IM does not deplete the CML stem cell population
which is maintaining the disease, and supports the hypothesis that CML stem
cells are resistant to IM and other TKIs (Graham et al. 2002; Copland et al.
2006; Jorgensen et al. 2007). This model further proposes that, as CML
progresses, the number of LSCs rises and the probability of a patient having
a resistance mutation also increases as a result of this larger population of
CML stem cells (Michor et al. 2005). In addition, it is suggested that the time
to treatment failure as a result of acquired resistance is dependent on the
growth rate of the CML stem cells. Therefore, based on the theories put
forward in this study, IM is extremely unlikely to cure CML patients, and
over time, the majority of patients will develop acquired resistance as the stem
cell population gradually expands. Thus, the development of strategies to
target the LSC population will be vital for the eventual eradication of CML.
The hypothesis proposed in the second study is rather more positive for
CML patients (Roeder et al. 2006). It suggests that the clinically observed
biphasic pattern of BCR-ABL transcript dynamics may be explained by a
selective effect of IM on proliferating CML stem cells. This model makes two
main assumptions. First, it assumes that IM inhibits proliferative activity and
induces death of proliferating CML stem cells and second, it assumes that
there is a large population of quiescent CML stem cells which are resistant to
IM due to their quiescent state as previously demonstrated (Graham et al.
2002). However, these quiescent CML stem cells retain the potential for
proliferation and are responsible for the rapid relapses seen after stopping
IM (Cortes et al. 2004; Mauro et al. 2004). This model predicts that, over time,
as quiescent CML stem cells gradually enter the cell cycle, they will proliferate
and become sensitive to IM. Therefore, levels of minimal residual disease
(MRD) will continue to fall over prolonged periods of IM treatment as
suggested by clinical data (Branford et al. 2004), and complete disease eradi-
cation may be possible if patients do not develop resistance mutations. The
model also proposes that promoting quiescent CML stem cells to enter the cell
cycle by using additional agents in combination with IM may enhance the
eradication of MRD in CML.
Although these two different hypothetical models of CML dynamics arrive
at different conclusions, they both highlight the importance of developing
drug combination strategies with IMor the newer agents (dasatinib, nilotinib,
and others) to eliminate the quiescent CML stem cell population. To this end,
our group has recently shown that the farnesyltransferase inhibitor, BMS-
214662, in combination with either IM or dasatinib results in a significant
reduction in the CML stem cell population in vitro (Copland et al. 2008) and
this combination is now being tested in a murine model, although the exact
mechanism of action remains to be elucidated. The use of HDAC inhibitors in
combination with IMas described earlier by Strauss et al. also appear to target
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