of the Max - MDC

Cancer, Stem Cells, and
Transcription Factors
Frank Rosenbauer
In recent years, great progress has been made in elucidating
the stem and progenitor cell hierarchy of the hematopoietic
system. The step-wise adoption of a cellular lineage identity
during hematopoietic differentiation is preceded by the ordered
reorganization of the chromatin, which is mediated by both
genetic and epigenetic factors. Transcription factors are key
determinants in the orchestration of cellular identity and differentiation
fates through expression modulation of specific target
gene subsets. Most transcription factors show narrow celllineage-
and stage-restricted expression patterns, indicating
the requirement for tight regulation of their activities.
Moreover, if dysregulated or mutated, these transcription factors
cause the differentiation block observed in many leukaemias.
Using mouse genetics as well as biochemical approaches,
our research group is particularly interested in the activities
and transcriptional regulation of main hematopoietic transcription
factors, such as PU.1, and in their functional interplay with
epigenetic chromatin modifiers.
The cancer stem cell concept
Analogous to the development of tissues from normal stem
cells, there is increasing evidence suggesting that malignancies
are sustained by cancer stem cells, a tumor subpopulation
which maintains the uncontrolled production of less
malignant neoplastic daughter cells (blasts). Cancer stem
cells appear to share important functions with normal stem
cells such as self-renewal, differentiation and long-term
survival. The existence of cancer stem cells is of great clinical
relevance since their unique “stemness” properties are
likely enabling them to escape conventional anti-cancer
therapy designed to target the fast cycling and highly proliferating
cancer blasts. This inability to eradicate cancer
stem cells might be responsible for the disease relapses frequently
observed in cancer patients.
Acute myeloid leukemia (AML) was the first cancer type for
which evidence was generated for the existence of a cancer
stem cell. By using transplantation assays of fractionated
human AML cells into murine xenograft models, a stem celllike
hierarchy was identified within the malignant cell population.
Depending on the transforming event, the cancer
stem cell population in AML is believed to arise either from
normal HSCs, whereby the activity of critical “stemness”
genes is preserved during transformation or from committed
progenitors, which regain stem cell functions. However,
the overall molecular events which underlie the formation
of cancer stem cells in AML and other human cancers remain
poorly understood.
Transcription factors orchestrate hematopoietic
stem cell differentiation
Differentiation of stem cells is associated with two fundamental
processes, reduction in self-renewal potential and
step-wise acquisition of a specific lineage identity. These
reciprocal processes are controlled by competing genetic
programs. If a stem cell is triggered to begin differentiating,
genes that maintain self-renewal are switched off,
whereas genes that enforce differentiation are switched on.
Further progenitor differentiation via a series of lineage
branching points is directed by altering groups of co-operative
and counter-acting genes, which together build a large
network of factors that determine cell fate. Interference
with the key components of this network can lead to loss of
lineage identity, enhanced infidelity, lineage reprogramming
and malignant transformation. Transcription factors
are those key components.
The formation of early hematopoietic progenitors from stem
cells is orchestrated by a relatively small number of transcription
factors. Among them are PU.1, CCAAT/enhancer
binding protein α (C/EBPα,), growth factor independent 1
(GFI1), interferon-regulatory factor 8 (IRF8), Runt-related
transcription factor 1 (RUNX1) and stem-cell leukemia factor
(SCL). Mice in which these genes have been knocked out
displayed profound hematopoietic defects.
Moreover, these transcription factors were shown to regulate
a broad range of pivotal target genes, thereby directly
programming precursors to differentiate along a complex
developmental pathway. A block in normal differentiation is
a major contributing factor towards the development of
solid tumors and leukemias and cells from leukemia patients
frequently harbor mutated or dysregulated transcription
factor genes. This suggests that altered transcription factor
activity is a major driving force behind the pathology of
transformation and the development of cancer stem cells.
Dynamic PU.1 expression in hematopoiesis and
leukemia
One of the main interests of our laboratory is to understand
how transcription factors direct normal stem cell functions,
92 Cancer Research