Biomedical Engineering Reference
In-Depth Information
PML-RARa, and PLZF- RARa activate the Wnt signaling pathway in hema-
topoietic cells (Muller-Tidow et al. 2004). Recently it has been shown that LEF1
may be important in leukemogenesis. Petropoulos et al. have demonstrated
expression of LEF1 in murine HSC and leukemia cells (Petropoulos et al. 2008).
Mice transplanted with bone marrow retrovirally transduced to express LEF1
or a constitutively active LEF1 mutant had serious abnormalities of normal
hematopoietic differentiation and developed B-ALL and AML, with the LSC
exhibiting lymphoid characteristics. This study demonstrates the importance of
normal LEF1 expression for routine hematopoietic development. Additional
studies suggest that Wnt signaling may also be important in the development of
some ALL subtypes, with inhibition of Wnt16 resulting in apoptosis in ALL
cells containing the E2A-Pbx1 fusion protein (Mazieres et al. 2005).
Interestingly, two inhibitors of the WNT signaling pathway have recently
been described which show efficacy in myeloid leukemias (Kavalerchik et al.
2006; Guzman et al. 2007a). The first of these, MCC-001, a marine sponge-
derived b-catenin antagonist, was demonstrated to inhibit the re-plating capa-
city of CML stem cells, derived from patients with advanced phase CML, at
doses which were non-toxic to normal HSCs (Kavalerchik et al. 2006). The
second compound, 4-benzyl, 2-methyl 1,2,4-thiadiazolidine 3,5-dione (TDZD-8),
a GSK-3b inhibitor, induced rapid cell death in both primary AML and blast
crisis CML cells (Guzman et al. 2007a). Further studies in a NOD-SCIDmouse
xenotransplantation model showed a 93% reduction in engraftment with
TDZD-8 for AML samples compared with an 11% reduction for normal cell
engraftment. Further studies are currently underway to fully elucidate the
mechanisms of action of these two novel compounds and further assess their
effect on the LSC compartment.
4.2 The Hedgehog Pathway in Leukemia
The hedgehog family consists of three highly conserved homologous proteins,
Desert (DHH), Indian (IHH), and Sonic Hedgehog (SHH). Murine studies
have demonstrated that hedgehog proteins have a role in the development of
many tissues and organs in the embryo and have been associated with a number
of different cancers (Chen et al. 2007). Recent microarray studies by our group
(Graham et al. 2007) and others (Radich et al. 2006) provide evidence that the
SHH pathway is active in CML stem cells and that the SHH pathway becomes
progressively more activated from chronic phase, through accelerated phase to
blast crisis (Radich et al. 2006). Furthermore, in this study, activation of the
SHH pathway correlated with CD34 expression, suggesting upregulation
within CML stem and primitive progenitor cells. In addition, very recent in
vitro and in vivo studies have shown that BCR-ABL enhances self-renewal of
HSC by activating the SHH pathway via upregulation of smoothened (Dierks
et al. 2007). Abnormal Hedgehog signaling may also be a feature of AML and
