232
Cancer Stem Cells
morphology of the leukemia cells and
clinical course resembled human CML
and AML in the hMRP8p210
BCR
/
ABL
mice
and the hMRP8p210
BCR
/
ABL
/hMRP8bcl-2
mice, respectively.
In a mouse model of high grade glioblas-
toma, enforced expression of the epider-
mal growth factor receptor (EGF-R) in
enriched populations of either Ink4a/Arf
null neuronal stem cells or Ink4a/Arf null
astrocytes led to malignant glioblastomas
when the cells were injected orthotopically
into mice. Notably, in the majority of cases
the transformed astrocytes appeared to ac-
quire an immature phenotype in the brains
of the mice, suggesting that there was
‘‘dedifferentiation.’’ However, such dedif-
ferentiation has never been conclusively
demonstrated. There are two other pos-
sible explanations for these results. First,
since it is unlikely that the cell culture
achieved 100% purity, it is possible that
the astrocyte tissue culture cells could
have contained a population of neuronal
stem cells that were transformed; these
stem cells could then have been respon-
sible for generating the tumors. In this
case, the immature appearance of the cells
could reflect a deregulated expansion of
the stem cell pool or early progenitor pool,
the result of which would be the overt
glioblastoma that was observed. Second,
it is possible that the tissue culture condi-
tions, in conjunction with the enforcement
of EGF-R expression, could have caused
the dedifferentiation of the astrocytes
in
vitro
, and that unless the astrocytes were
grown in tissue culture ±rst they could
not later give rise to glioblastomas in an
animal.
The human and mouse observations
support the notion that oncogenic muta-
tions accumulate in the stem cells. Expres-
sion of the mutated gene by progenitors
downstream of the stem cells, or an addi-
tional mutation in a short-lived progenitor
cell, can lead to neoplastic transformation.
These observations have implications for
targeted therapies.
It is possible that only a minority of
the mice, whose progenitors express BCR-
ABL, develop leukemia because the pro-
genitors must acquire an additional muta-
tion that causes deregulated self-renewal.
There are two lines of evidence that sup-
port this hypothesis. First, expression of
bmi-1
is necessary for the self-renewal of
adult HSCs; blast cells of patients with
AML express large amounts of this protein.
While expression of
HoxA9
and
Meis1
in-
duces transplantable AML in normal mice,
expression of these genes in the absence
of Bmi-1 does not. This suggests that, in
at least some leukemic blasts, a mutation
activating
bmi-1
must take place in order
to confer self-renewal capability onto the
blast cells. Second, deregulated
β
-catenin
signaling occurs in many
de novo
human
cancers and causes cancer in transgenic
mouse models. Because expression of a
constitutively active
β
-catenin can promote
the self-renewal of normal HSCs and stem
cells from other tissues, it is possible that
its activation promotes self-renewal of can-
cer cells in these tissues as well. On the
basis of these data, it is clear that achieving
an understanding of the molecular regula-
tion of self-renewal in both normal stem
cells and cancer cells could lead to more
effective therapies for cancer.
5.3
Targets for Malignant Transformation in
Hematopoietic Malignancies
The systems in which the target cells for
transformation are best understood are
hematopoietic malignancies; this is be-
cause the developmental hierarchy of the
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