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promyelocytic leukemia (APL) the characteristic chromosome abnormality (a
15:17 translocation) is not found in hematopoietic stem cells; it is found in
committed progenitor cells (Turhan et al. 1995). In a mouse leukemia model,
myeloid progenitor cells have the ability to induce malignancy if manipulated to
overexpress Bcl-2 in conjunction with the translocation-induced oncogene
BCR/ABL [B-18], suggesting that early oncogenic manipulation could cause a
more committed progenitor cell to gain tumorigenic capabilities. Additionally ,
the MLL-AF9 fusion protein has been shown to induce granulocyte-macro-
phage progenitor cells to initiate leukemia in mice (Krivtsov et al. 2006). These
same progenitor cells have also been shown to take on self-renewal capabilities
via the Wnt/b-catenin signaling pathway (Jamieson et al. 2004), making them
candidates for originators of pCSC populations. Granulocyte-macrophage
progenitors are particularly interesting in that when transformed by MLL-
AF9 they retain a gene expression profile indicative of progenitor cells and do
not take on a hematopoietic stem cell signature despite pCSC-like qualities
(Krivtsov et al. 2006). Outside of the hematopoietic system, similar evidence is
mounting that neural progenitors may give rise to brain tumors (Vescovi et al.
2006) and shows that the role of progenitor cells in oncogenic transformation is
likely not merely hematopoietic cancer-specific.
The stronger evidence for progenitors in pCSC formation could simply
reflect a bias in experimental design. It is more difficult to find and study
adult stem cell populations and the possibility remains that both types of cells
could be the source pre-neoplastic cells which sustain further mutation to
become fully tumorigenic. Malignant gliomas can be induced from either neural
stem cells or transformed astrocytes if the genes for Arf and Ink4a are inacti-
vated in the presence of EGFR activation (Bachoo et al. 2002). Since these
lesions are all highly metastatic, the question remains as to whether or not
induction of stem cells versus progenitors can account for tumors of varying
metastatic phenotypes. Some precedence for this exists in mammary epithelial
cells. Expression of H-ras-v12, hTERT, and SV-40 large T antigen in different
mammary cell types results in tumors with different metastatic characteristics,
but only when cultured under different conditions (Ince et al. 2007)
pCSC function could also be a more complicated progression involving both
types of cells. A stem cell could potentially undergo an early transformative
event and give rise to progenitor cells which only then sustains further muta-
tions necessary for malignancy. For example, breast cancer tumor cells expres-
sing the marker CD44 + are closely related to CD24 + cells. CD24 + cells appear
to have arisen from CD44 + precursors and sustained further mutations giving
rise to a new clonal population. The CD24 + cells carry an initial oncogenic
transformation shared with CD44 + cells plus additional novel mutations
(Shipitsin et al. 2007). Unfortunately, in experiments that investigate a single
oncogenic variable, complex interactions such as those seen in breast cancer
may not be detectable. For instance perturbing various cell types with specific
oncogenic challenges may not reveal the natural step-wise process leading to
metastatic cells. Moving beyond analysis of tumor heterogeneity to find the
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