Oncogene (2004) 23, 7290–7296
& 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00
www.nature.com/onc
Stem cells, aging, and cancer: inevitabilities and outcomes
Deborah R Bell1 and Gary Van Zant*,1,2
1
Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA; 2Department
of Physiology, Markey Cancer Center, University of Kentucky, Lexington KY 40536-0093, USA
Given the unique abilities of a stem cell to self-renew,
differentiate, and proliferate, it is no wonder that they are
critically important to an organism during development
and to maintain homeostasis. Likewise, when something
goes awry within a stem cell, it is likely to have farreaching effects, since stem cells persist throughout the
lifetime of the individual. Two significant biological
phenomena that involve stem cells are the inevitable
process of aging and a major health issue whose incidence
increases with aging: cancer. In this review, we summarize
evidence and theories concerning these two stem cell
processes. The inability of stem cells to be passaged
indefinitely in mice and the data supporting regular
replication of the quiescent stem cell pool are discussed.
Further, the current evidence indicating a stem cell origin
of acute myeloid leukemia, including examples from both
experimental mouse models and human clinical samples, is
evaluated. Finally, we propose a model in which aging of
the stem cell population of the hematopoietic system in
particular can create conditions that are permissive to
leukemia development; in fact, we suggest that aging is a
secondary event in leukemogenesis.
Oncogene (2004) 23, 7290–7296. doi:10.1038/sj.onc.1207949
Keywords: stem cell; aging; leukemia; self-renewal;
AML
Aging and stem cells
Theories of stem cell aging
Single-celled organisms and simple multicellular animals
have lifespans commensurate with their cellular longevity. The evolution of highly specialized organ systems
in complex organisms enabled organismal longevity that
greatly exceeded the lifespan of almost all of its
composite cells. This strategy was dependent on a
source of cells to replace those lost by attrition during
a lifetime of wear and tear. It is now known that stem
cells located throughout the body in multiple organs
serve this purpose and have lifespans that may equal or
*Correspondence: G Van Zant, University of Kentucky, Markey
Cancer Center, 800 Rose St, Rm cc 414, Lexington, KY 40536-0093,
USA; E-mail: [email protected]
exceed those of the organism (Harrison, 1973).
However, because of the long life of stem cells and
their potentially long replicative histories, they are subject
to damage from several intracellular and extracellular
sources. For example, the long-term exposure to reactive
oxygen species (ROS) largely generated as a by-product
of cellular metabolism is known to have deleterious
effects on numerous cellular macromolecules, including
proteins, nucleic acids and lipids. Although damages to
each of these classes of molecules are individually
important, and may be synergistic collectively, we wish
to limit our discussion here to the nucleic acids and
proteins that make up chromatin. A second major
cause of damage may owe to the repetitive rounds of
replication stem cells undergo during a lifetime. DNA
replication results in numerous copy errors, the correction of which cells have evolved elaborate proofreading
and editing mechanisms. Since these mechanisms’ may
be eroded with time (for example, as a result of oxidative
damage), genetic damage may result and accumulate.
One strategy for stem cell populations to obviate the
risk of damage from long replicative histories is through
clonal succession, wherein the vast majority of the
population is homeostatically maintained in a quiescent state, and one or at most several stem cells are actively simultaneously supplying differentiated cells (Kay,
1965). In this way stem cells would replicate only as they
assume the role of an active clone, and since they would
continue to supply differentiated progeny through
replication and differentiation until the clone was
extinguished, they would not rejoin the pool of quiescent
stem cells. Thus, the strategy of clonal succession
supposes that the stem cell population would decrease
in size with age as the number of used and extinguished
clones grows. Crises during a lifetime requiring increased generation of differentiated cells would accelerate the rate of succession. To compensate for loss, one
could postulate that a sufficiently large stem cell
population could provide a buffer to not only meet the
needs of homeostasis but also meet the needs of the
crises as well.
Data obtained in experiments in which the thymidine
analog bromodeoxyuridine (BrdU) was administered
continuously to mice cast doubt on successive activation
of stem cell clones, at least in blood cell formation. In
these experiments, after as little as one month, more
than half of the hematopoietic stem cells had incorporated BrdU, indicating that they had undergone at least
The importance of stem cells in aging and leukemia development
D R Bell and G Van Zant
7291
one replication during that period; the population was
nearly completely labeled in two months (Pietrzyk et al.,
1985; Bradford et al., 1997; Cheshier et al., 1999). All
stem cells apparently replicate on a regular and frequent
basis, thus dispelling one of the tenets of the clonal
succession theory. However, the BrdU experiments do
not address the issue of whether or not stem cells follow
a pattern of sequential usage, but studies in vivo in
mouse chimeras show that many, if not all, of
hematopoietic stem cells simultaneously contribute to
blood formation (Harrison et al., 1987).
Evidence supporting aging of stem cells
In the analogy used to introduce this section, it might be
argued that single-celled organisms, rather than having
a limited longevity, live forever because they reproduce
by fission, and daughter cells of the next generation are
composed of the cellular components of the previous
generation. In mammals, stem cells of the germ line are
the only cells that maintain the link through organismal
generations, and since sexual reproduction has evolved,
two lineages of germ cells are responsible for the
composition of each individual. Thus, the entire human
race can be traced back to one ancestral couple. In an
alternative model to clonal succession, a characteristic
of adult stem cells that sets them apart from other
somatic cells is their ability to replicate in the strictest
sense: to generate at least one daughter cell that has
equivalent developmental potential, a phenomenon
known as self-renewal. It is this property, unnecessary
in clonal succession, that has been hypothesized to
ensure an unlimited supply of stem cells, irrespective of
demands put on the system by aging or stress caused by
injury or disease. In an experimental test that in some
ways parallels the intergenerational span of germ line
stem cells, hematopoietic stem cells have been serially
transplanted through a succession of lethally irradiated
hosts, and the originally engrafted stem cells must
repopulate the hematopoietic systems of a series of
‘generations’. Unlike germ line stem cells, adult stem
cells such as those of the hematopoietic system are
incapable of sustaining an indefinite line of generations
(Siminovitch et al., 1964). Rather, after no more than
four or five generations, they are no longer able to
sustain a myeloablated recipient. Although stem cell
transplantation may not accurately reflect organization
and usage of the stem cell population in unmanipulated
animals or humans, it is the measure of stem cell
function most consistent with the natural role of stem
cells in vivo. The limited ‘lifespan’ of hematopoietic stem
cells during serial transplantation, at least within the
context of the experimental model, suggests that stem
cells age. Correlates of cellular aging such as telomere
shortening have been shown to accompany the decline
in stem cell function in both serial transplantation and
natural aging (Vaziri et al., 1994; Allsopp et al., 2001).
In contrast, the telomere lengths of embryonic stem cells
and germ line stem cells do not change with serial
passage in vitro and age, respectively (Counter, 1996;
Liu et al., 2000). Abundant expression of telomerase in
embryonic, germ line and hematopoietic stem cells may
account for at least part of the resistance to telomere
erosion, but in hematopoietic stem cells either telomerase expression is not sufficient quantitatively or other
mechanisms contribute to their aging (Allsopp et al.,
2003).
Stem cell renewal and aging
Within the last few years, several regulators of selfrenewal in the hematopoietic stem cell population have
been identified: two Hox gene products, HOXB4 and
HOXA9 (Sauvageau et al., 1995; Antonchuk et al.,
2002; Thorsteinsdottir et al., 2002) and, more recently,
PBX1 (Krosl et al., 2003) and the product of the Bmi-1
gene (Lessard and Sauvageau, 2003; Park et al., 2003).
Overexpression of these genes in hematopoietic stem
cells, through transduction via viral vectors (HOXB4
and HOXA9), results in stem cells capable of enhanced
renewal and, at least under some conditions, no evidence
of tumorigenic transformation. If stem cell renewal
limits normal functioning of adult tissues, which in turn
limits organismal longevity, these models provide a test
of the potential role of stem cells in aging and longevity.
Enhanced stem cell renewal may prolong homeostatic
tissue renewal with age and provide a buffer against
replicative stresses that may occur. Although the studies
to date have principally focused on the hematopoietic
stem cell system, it is conceivable and perhaps likely that
the Hox genes B4 and A9, and Bmi-1 affect the renewal
of other adult stem cell populations as well. Therefore, a
simple and straightforward test of this hypothesis may
be to determine the effect of enhanced stem cell selfrenewal on tissue replenishment during aging and on
organismal longevity.
Impact of aging stem cells on health
Human aging is accompanied by what on the surface
seem to be subtle changes in hematopoiesis, including
decreased marrow cellularity, anemia, and blunted
immune responses (Lipschitz et al., 1981). However,
far less subtle age-related changes in blood formation
become apparent in response to hematopoietic stress.
Response may not only be slowed, but recovery may be
incomplete even after long periods of time (Botnick
et al., 1982; Marley et al., 1999; Kim et al., 2003). For
example, hematopoietic reserves are depleted during
aging and account for significant morbidity and mortality in patients undergoing myeloablative cancer
therapies. During homeostatic blood formation in the
elderly, there is growing awareness that what have been
regarded as subtle change only appears so in the context
of normal values of young populations. Specifications of
a significant proportion of the human population is
anemic for reasons not easily explained by comorbidity
factors such as iron or folate deficiencies (Balducci, 2003;
Ershler, 2003; Rothstein, 2003). Unexplained anemias
account for nearly half of those seen in older patients,
and the older the population, the greater the number of
unexplained anemias becomes (Penninx et al., 2003;
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The importance of stem cells in aging and leukemia development
D R Bell and G Van Zant
7292
Cesari et al., 2004). Although the severity of the
anemia is modest and in most cases goes untreated, its
symptoms in the elderly are out of proportion to the
decline in hemoglobin. There may be multiple causes for
the amplified effects of anemia in the elderly and for
anemia itself. With respect to the latter, it may reflect a
dysregulated red cell production in the bone marrow.
Since stem cells are ultimately responsible for erythropoiesis, an important but unresolved question is the
possibility that anemia in the elderly is, in many cases,
a reflection of ‘smoldering’ myelodysplasia. This possibility brings us back to the point first made in this review;
namely, that age-related accumulation in chromatin
damage, especially in stem cells that are capable of
passing such defects on to abundant progeny, may
account for the dramatic increase in cancer seen after
the age of 50.
Stem cells and cancer
The importance of stem cells in acute myelogenous
leukemia (AML)
The unique ability of a stem cell to self-renew,
differentiate into multiple lineages, and extensively
proliferate underlies the crucial role of these cells in
human development and homeostasis. In fact, most
major organ systems of the body have been shown to
contain and rely upon a pool of stem cells specific to that
organ system, including the hematopoietic, central
nervous, and hepatic systems (McKay, 1997; Clarke
et al., 2000; Vicario-Abejon et al., 2000; Weissman,
2000; Hawke and Garry, 2001; Toma et al., 2001; Vessey
and de la Hall, 2001). The hematopoietic stem cell, or
HSC, has been isolated and studied in detail in both
man and mouse, and these cells are already widely used
in clinical treatments as the critical component of bonemarrow transplantation therapies.
Cancers of the hematopoietic system, or leukemias,
have been shown to originate from and be sustained by
cancer stem cells. Leukemias provide the most convincing data that normal stem cells can become cancer stem
cells through the acquisition of mutations, and it is this
leukemic stem cell (LSC) that is responsible for the
disease (Reya et al., 2001). Studies of human AML have
begun to define the genetic alterations and chromosome
translocations associated with the various subtypes of
the disease (Dash and Gilliland, 2001). AML is a very
heterogeneous disease clinically and includes many
subtypes (M0–M7) as defined by the French–American–British (FAB) classification system (Mirro, 1992).
Despite this heterogeneity, the leukemias are quite
similar at the level of the stem cell and also share many
of the same immunophenotypic markers as normal
HSCs (Lapidot et al., 1994; Bonnet and Dick, 1997).
With the advent of improved methods of detection and
isolation of stem cells (such as fluorescence activated cell
sorting, or FACS), it is now possible to analyze the
functional and molecular characteristics of both normal
HSCs and LSCs. Recent reports formally have described
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the existence of LSCs in AML and strongly suggest that
these LSCs give rise to the disease (Jordan, 2002).
Specifically, when CD34 þ /CD38 cells, previously
defined as containing the stem cell population of normal
bone marrow (BM), were isolated from the BM of
patients with AML and transplanted into the nonobese
diabetic/severe combined immunodeficient (NOD/
SCID) mouse, leukemic disease was evident and
transferable (Bonnet and Dick, 1997). This indicates
that, just like the normal HSC, the LSC also displays the
cell surface marker phenotype of CD34 þ /CD38.
Other evidence supporting the stem cell origin of
AML comes from studies on the various subtypes of
the disease. As mentioned previously, AML subtype
classification is based upon the morphologies and
genetic abnormalities of the leukemic cells (FAB
subtypes) (Brendel and Neubauer, 2000). Interestingly,
the AML subtypes M0, M1, M2, M4, and M5 all
contain LSCs with similar immunophenotypes, even
though each of these subtypes of leukemia displays a
very different clinical disease (Guzman and Jordan,
2004). While the phenotypically identical LSCs
(CD34 þ /CD38) from each of the AML subtypes,
when transplanted into NOD/SCID mice, contained the
leukemia-initiating cells, the resulting disease was
similar to that observed in the donor patient (Wang
et al., 1998). These results indicate that the initially
transformed cell was a primitive stem cell that took the
wrong developmental pathway, presumably depending
upon the mutation that occurred. All of these data point
to a transformed stem cell source of leukemia.
The ‘two-hit’ model of leukemogenesis
An important corollary to this discussion of a stem cell
origin of AML is the theory that cancer, in general,
results from a series of genetic changes that, over time,
confer unique properties to a cell that lead to a
progression from normalcy to malignancy (Hanahan
and Weinberg, 2000). These genetic alterations include
but are not limited to independence in growth factor
signaling, escape from apoptosis, and endless ability to
replicate. Likewise, AML progression is theorized to
result from a stepwise accumulation of genetic mutations. This buildup of mutations takes place over the
lifespan of an individual, which is why AML is more
than three times as likely to occur in someone aged 65
years versus an individual who is 35 years old (NCI,
2000). Indeed, the median age at diagnosis of patients
with AML is 65 years (Lowenberg et al., 1999). Given
that the origin of AML is a hematopoietic stem cell that
has undergone oncogenic mutations, it is reasonable to
propose that an aging stem cell is a likely target for this
leukemic transformation.
Acute myeloid leukemias are composed of leukemic
cells that not only have proliferation and/or survival
advantages over other cells of the hematopoietic system
but also have diminished/poor differentiation as
compared to normal cells (Deguchi and Gilliland,
2002). In contrast to solid tumors that typically contain
point mutations, gene amplifications and/or deletions,
The importance of stem cells in aging and leukemia development
D R Bell and G Van Zant
7293
leukemias are commonly associated with chromosomal
translocations that juxtapose two unrelated genes and
their products that lead to aberrant expression or
function of the fusion protein. Studies of human AML
samples indicate that most translocations involve
transcription factors or components of the transcriptional activation complex (Deguchi and Gilliland, 2002).
Recurring examples include translocations involving
both subunits (AML1 and CBFb) of core-binding factor
(CBF) (Liu et al., 1993; Romana et al., 1995), MLL gene
rearrangements (Thirman et al., 1993), Hox family
members (Nakamura et al., 1996; Raza-Egilmez et al.,
1998), and the coactivators CBP and p300 (Giles et al.,
1997; Rowley et al., 1997). Specifically, the following
chromosomal translocations involving transcriptional
elements have been detected in and cloned from human
AML samples: CBFb/MYH11 (Claxton et al., 1994),
MLL/CBP (Taki et al., 1997), MLL/ENL (Thirman
et al., 1994), Nup98/HoxA9 (Borrow et al., 1996),
Nup98/HoxD13 (Pineault et al., 2003), and, frequently,
AML1/ETO (Golub et al., 1994). Significantly, when
these oncogenic translocations are expressed in murine
bone marrow experimental models, a myeloid leukemia
is usually not evident for 6–12 months (Dash et al.,
2002). In these models of leukemia, this is taken as
evidence to support the requirement of additional
mutations to cause full acute leukemic disease.
The current ‘two-hit’ model of AML cites mutation in
a cellular kinase that results in a constant growthpromoting signal, and mutation in a hematopoietic
transcription factor that leads to disrupted developmental potential as the important elements driving
leukemogenesis (Dash and Gilliland, 2001; Deguchi
and Gilliland, 2002). Clinically, support for the acquisition of cooperating mutations in the development of
AML is well documented. In nearly all cases of chronic
myeloid leukemia (CML), a translocation exists that
constitutively activates a tyrosine kinase. Common
translocations associated with CML include BCR/
ABL, TEL/ABL, TEL/PDGFbR, and TEL/JAK2
(Deguchi and Gilliland, 2002). Expression of these
constitutively active kinases results in increased proliferation and/or survival of affected cells without a block
in cellular differentiation. It is the subsequent gain of
mutations involving transcription factors that provide
the differentiation block and cause the onset of acute
disease. Examples of CML progression to AML (or
CML blast crisis) provide supporting evidence for this
hypothesis. Cases of CML patients with BCR/ABL
positive disease (activated kinase) progressing to acute
leukemia with ensuing acquisition of either the Nup98/
HoxA9 or AML1/ETO translocations (transcription
factors) are documented (Golub et al., 1994; Yamamoto
et al., 2000). To further illustrate this point, the 8;21
chromosomal translocation, which encodes the AML1/
ETO fusion protein, is a recurring genetic abnormality
in AML that alters gene expression. This fusion gene is
detectable in the stem cells of AML patients, but
interestingly, it also remains detectable in stem cells
from patients in long-term remission (Miyamoto et al.,
2000). This indicates that other genetic events, besides
the AML1/ETO translocation, are necessary for progression and lethality of leukemia. Finally, and probably most
compelling, are data obtained in a study of twins who
developed AML due to the TEL/AML1 translocation.
Upon analysis of this unique biological phenomenon, it
was determined that one TEL/AML1 clone was transmitted between the twins in utero. Despite this shared,
identical mutation, neither twin was born with leukemic
disease. In fact, both twins developed AML later in life
but at greatly differing times (Ford et al., 1998; Wiemels
et al., 1999a, b). All these data point to the need for
multiple cooperating mutations during leukemogenesis.
It should be noted, however, that translocations
involving tyrosine kinases are rare in acute leukemias.
While the BCR/ABL fusion is responsible for the
majority of cases of CML, similar fusions of activated
kinases are not usually found in AMLs. How then is a
signal for increased growth and/or survival mediated in
these cells? It has recently been observed that point
mutations in certain tyrosine kinases can cause constitutive activation of these growth regulators. In particular, Flt3 tyrosine kinase internal tandem duplications
(ITD) and activating mutations are widely seen; in fact,
Flt3 activation is described as the most common
alteration in AML (Mizuki et al., 2000; Tse et al.,
2000). In addition, up to 5% of all cases of AML
contain mutations that cause constitutive activation of
the kinase c-Kit (Care et al., 2003). So, the presence of
one of these active kinases in addition to the commonly
seen transcription factor translocations corresponds well
with the two-hit theory of leukemogenesis.
Aging as the second event in leukemia progression
The large amount of work summarized in this review
corresponds strongly with a model of multistep leukemogenesis, in which the main culprits of disease consist
of an altered transcription factor that causes a
differentiation block, and of an activated kinase that
can provide limitless growth and survival signals. The
combination of these events is critical to disease
development. However, as evidenced by the increase in
leukemia incidence with advancing age, and the long
latency of AML development in mouse models, these
detrimental mutations obviously take place over a long
period of time. Aging, therefore, must also be a key
player in this scenario. Since stem cells have been shown
to be the source of AML, and due to the effects of aging
on the stem cell population of an individual, we favor a
model of AML in which aging may be considered a
secondary age-related event in leukemogenesis
(Figure 1). However, the models in Figure 1a and b
are not necessarily mutually exclusive. For the sake of
simplicity, models a and b are shown as separate events.
But secondary mutations (a) that help drive leukemogenesis may be direct results of the age-related changes
brought about by increasing age (b). Effects on DNA
repair mechanisms and repeated exposure to environmental insults, both internal and external, may cause
enough genomic instability to permit the formation, and
escape from detection, of the translocations and point
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The importance of stem cells in aging and leukemia development
D R Bell and G Van Zant
7294
a
Current “two-hit” theory of leukemogenesis
initial mutation
secondary mutation
leukemia
normal HSCs
b
transcription factor:
AML1/ETO
MLL/CBP
Nup98/HoxA9
tyrosine kinase:
BCR/ABL
Flt3
c-Kit
Age as a secondary event in the development of leukemia
secondary
age-related
event
initial mutation
*
Long life
normal HSCs
?
Lon
g lif
e
exposure to insults:
ROS, DNA damage
decreases in:
homing of stem cells
developmental potential
immune system function
leukemia
microenvironment changes
*
age-related events
Figure 1 Models predicting the progression of leukemia. (a) Current theory and data suggest that development of AML depends on
at least two cooperating mutations, usually in a transcription factor, which provides a block to differentiation, and a tyrosine kinase,
which causes constitutive activation of the kinase and a strong growth-promoting signal. Either mutation can be the ‘initial’ event in
leukemogenesis. (b) The model in panel (b) suggests that the aging of an individual can create cellular conditions conducive or
permissive to AML development. Such conditions, either in conjunction with an initial mutation (top scenario in b) or alone and over a
lifetime (bottom scenario in b), include exposure to environmental insults, accumulated DNA damage, and/or decreased immune
system surveillance
mutations/duplications commonly seen in human
AMLs. In this regard, aging would provide and promote
conditions permissive to leukemic transfomation. Aging
stem cells also display decreased developmental potential, which could be similar to the effects of a mutated
transcription factor and skew the differentiation of
progeny. Furthermore, decreased monitoring by the
immune system, another issue in older individuals, may
allow disease to progress more efficiently and aggressively. Hence, age may be just as important a factor in
AML development as the altered genes themselves.
Final thoughts
It is the purpose of the authors in this review to provide
evidence supporting the models of both aging and
leukemic transformation of stem cells, and further to
demonstrate how these models are related. The identification of malignant stem cells in cancers other than
the hematopoietic system, such as breast and brain,
provides increasing evidence consistent with a general
model of stem cell origin of disease.
It is not surprising that age is the single most
important prognosticator of developing cancer. To
the extent that at least some, and perhaps many
malignancies are stem cell-derived, cancer may provide
Oncogene
some of the strongest evidence supporting the concept of
stem cell aging. However, the notion that stem cells
show age-related decrements in function remains controversial (Iscove and Nawa, 1997). Readers are directed
to recent reviews expanding on the issues surrounding
stem cell aging and their potential effects on malignant
transformation (DePinho, 2000; Geiger and Van Zant,
2002; Liang and Van Zant, 2003; Van Zant, 2003; Van
Zant and Liang, 2003). The authors’ laboratory has
used a forward genetic approach in mice to identify
quantitative trait loci that regulate a number of stem cell
properties, including their numbers, self-renewal, and
aging patterns. Two early observations led us to
undertake this effort. First, wide variation was observed
among inbred mouse strains with respect to key
parameters of early hematopoietic cells (Van Zant
et al., 1983). Second, embryo-aggregated cellular chimeras (allophenic mice), composed of cells of two
strains, showed wide variation in hematopoietic phenotypes, and shed light on several issues (Van Zant et al.,
1990). Stem cells of the short-lived DBA/2 strain ceased
hematopoiesis in the chimeras at a time commensurate
with their mean lifespans. Thereafter, hematopoietic
cells became wholly derived from the longer-lived
C57BL/6 strain. These results demonstrated in a
convincing manner that stem cells age differentially.
The importance of stem cells in aging and leukemia development
D R Bell and G Van Zant
7295
Since the two stem cell populations coexisted throughout embryogenesis and adult life in precisely the same
bone marrow milieu, the differential aging had to be
regulated by cell-intrinsic (genetic) mechanisms rather
than extrinsic, environmental differences.
Armed with this knowledge and the growing realization of the extensive natural variation between mouse
strains, we and others have made use of such interstrain
differences in experiments to identify the underlying
responsible genes (Muller-Sieburg and Riblet, 1996;
Chen et al., 2000a, b; de Haan et al., 1997, 2000; de
Haan and Van Zant, 1997, 1999a, b; Geiger et al., 2001,
2004; Morrison et al., 2002). These are works in progress
and point upto the difficulties in unraveling complex
quantitative traits relevant to hematopoiesis (Biola et al.,
2003). However, recent genetic advances such as
microarrays, complete genome sequences of several
mouse strains, including the C57BL/6 and DBA/2
strains, and more advanced bioinformatics tools have
led to significant progress in the last few years. An
important issue for the future is to relate the genes
important for stem cell phenotypes, aging, and malignant transformation. There is obviously wide natural
variation in the latency of carcinogenesis and progression of the disease in different individuals and mouse
strains, even in the latter when cancer is experimentally
induced by the same genetic translocation. The search
for, and manipulation of, the underlying modifier genes
represent an important but largely untapped approach
to cancer therapy. Until now, the genetic complexity of
sifting through the genome in search of modifiers, let
alone understanding the molecular pathways by which
they wielded their influence, was difficult, if not
impossible. The genetic tools for such experimental
studies are now in place and are being used in this effort
and it is predicted that significant advances are forthcoming in the near future.
Acknowledgements
We acknowledge the support of Grants R01 AG016653, R01
AG20917, and R01 AG022859 from the National Institutes of
Health.
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