of the Max - MDC

Cell Differentiation and
Tumorigenesis
Achim Leutz
Hematopoietic stem cells (HSC) in the bone marrow give rise to cells that differentiate into several
short-lived blood cell types (Figure 1). Hematopoietic transcription factors concertedly control
these processes. Mutations in key transcription factors may dysregulate hematopoiesis and cause leukemia.
A major pursuit in experimental hematology, leukemia research, and stem cell research is to untangle
the underlying transcription factor network, to disclose functional interactions between its components,
and to reveal the mechanisms that regulate stem cell biology and leukemic transformation.
Figure 1. A hierarchical model of
hematopoiesis.
Hematopoietic stem cells self renew (circular
arrow) and give rise to restricted progeny.
Multipotent progenitors may generate cells
of all lineages but have lost their long term
stem cell capacity. Common lympoid- and
myeloid precursor cells are further restricted.
Finally, lineage restricted precursors
give rise to mature blood cell types. Binary
decisions in the commitment phases are executed
by distinct hematopoietic transcription
factors. Note that progenitor compartments
expand as “transit amplifying cells”
whereas differentiated cells are growth arrested.
Background: Hematopoietic stem cells,
transcription factors, & differentiation
Hematopoiesis navigates along hierarchical cell differentiation
routes, with few slowly self-renewing hematopoietic
stem cells (HSC), strongly proliferating precursor cells
undergoing lineage commitment, and large numbers of terminally
differentiated cells. Self-renewal, proliferation, and
cell differentiation programs are interconnected through
signaling cascades and gene regulatory proteins (transcription
factors) that suppress or activate developmentally
important genes. The transcription factor network contains
early factors, essential to stem cells or progenitors, such as
the basic helix-loop-helix protein SCL, or the c-Myb protein,
and additional transcription factors of various protein families,
such as C/EBPs, that cooperate with the early factors
during cell differentiation. Mutations may disrupt the normal
function of signaling cascades or the function of key
transcription factors and cause leukemic conversion by
maintaining or reinstalling self-renewal properties and inhi-
88 Cancer Research