of the Max - MDC

such as self-renewal and differentiation, how they program
precursors to adopt a certain lineage choice and how disruption
of transcription factor activity leads to cancer
(stem) cell transformation. Using both transgenic and
knockout mouse models, we are particularly interested in
discovering crucial molecular up- and downstream mechanisms
that regulate the expression and function of transcription
factors. A current research focus in our laboratory
is on PU.1. The Ets-family member PU.1 is essential for both
myeloid and lymphoid lineages. PU.1 knockout mice exhibit
early lethality and lack of B-lymphocytes and mature
myeloid cells in fetal livers. In addition, PU.1 is important
for HSC self-renewal and differentiation into the earliest
myeloid and lymphoid progenitors. Furthermore, PU.1 must
be properly downregulated in early thymocytes to allow normal
T cell development, since enforced PU.1 expression in
thymic organ cultures completely blocked T cell production.
It was shown that graded changes in PU.1 concentrations
have drastic effects on lineage fate decisions. Therefore, a
greater understanding of PU.1 gene regulation is the key to
deciphering its role in normal hematopoiesis and malignant
transformation.
We reported that the proximal PU.1 gene promoter is insufficient
for reporter gene expression in transgenic mice, indicating
that additional elements are required for PU.1 gene
regulation in vivo. In support of this, several clusters of
DNaseI hypersensitive sites harboring potential regulatory
elements were identified in the PU.1 gene locus. Inclusion
of the most distal cluster, located 14 kilobases upstream of
the PU.1 gene transcription start site (referred to here as
URE for upstream regulatory element), with the proximal
PU.1 promoter resulted in reporter gene expression in
Model of leukemia development from blocked
myeloid differentiation. The normally short-lived
intermediate myeloid progenitors undergo rapid proliferation
before they differentiate into functional
immune cells. The balance between proliferation and
differentiation is tightly controlled by stage-specific
transcription factors. If dysregulated or mutated,
these transcription factors fail to induce differentiation
and thus can cause a prolonged proliferation
phase. This might place the progenitors at higher
risk to ultimately developing a true leukemia due to
the random accumulation of additional co-operating
events.
Cancer Research 93