Biomedical Engineering Reference
In-Depth Information
study by Huntly et al. also demonstrated that, in the same model, transduction
with BCR-ABL did not confer self-renewal properties to the cells (Huntly et al.
2004), indicating that secondary mutations are required in addition to BCR-ABL
for committed progenitor cells to develop self-renewal characteristics as shown
by Jamieson et al. (Jamieson et al. 2004). The mechanisms underlying this
difference in the ability of oncogenes to bestow self-renewal properties on a
leukemia cell remain to be elucidated.
4 Targeting Self-Renewal in LSC: Potential Therapeutic Strategies
The understanding of self-renewal in normal and leukemic HSC is a rapidly
expanding field of research at present. The pathways involved in the self-
renewal of HSC and LSC are broadly similar and include the Wnt, Hedgehog,
and Notch pathways, the NF-kB, HOX, and polycomb gene families, PTEN
and telomerase.
4.1 Wnt Signaling in Leukemia
b-catenin is central to the Wnt signaling pathway. Wnt stimulation results in
accumulation of b-catenin and its translocation to the cell nucleus where it
interacts with T-cell factor/lymphoid enhancer factor (TCF/LEF1) to regulate
genes which are important in embryonic development and cell proliferation.
There is increasing experimental evidence that the development of both myeloid
and lymphoid leukemias may be dependent on Wnt signaling. As described
above (Jamieson et al. 2004), in blast crisis CML compared to earlier stages of
disease, the committed granulocyte-macrophage progenitor cell acquires the
ability to self-renew in vitro in association with activation of b-catenin, a
protein of the WNT signaling pathway which is associated with cell differentia-
tion, proliferation, and death. Furthermore, very recently, research has shown
that progression to blast crisis CML is associated with missplicing of GSK-3b in
granulocyte-macrophage progenitors, allowing unphosphorylated b-catenin to
contribute to self-renewal (Abrahamsson et al. 2007). More recent studies in
normal HSC and both CML and AML have demonstrated a central role for
Wnt signaling in normal hematopoiesis and leukemogenesis. Zhao et al.
demonstrated that although b-catenin-deficient mice can form HSCs, the cells
produced are unable to maintain hematopoiesis in the long term (Zhao et al.
2007). In addition, the absence of b-catenin prevented mice developing BCR-
ABL
+
CML, but not BCR-ABL
+
ALL, suggesting that b-catenin may be
preferentially required for leukemias that originate in HSCs but not committed
progenitors.
In AML, studies have shown that there is constitutive activation of the Wnt
pathway (Simon et al. 2005) and that translocation products, e.g., AML1-ETO,
