The production of mature blood cells,
hematopoiesis, involves a carefully orchestrated series of events involving
self-renewal and differentiation of primitive pluripotent stem cells. This program
aims to understand the processes by which normal hematopoiesis becomes
dysregulated in the development of bone marrow failure or leukemia.
Although
hematopoiesis is controlled at the level of self-renewal, proliferation,
survival and differentiation, the specific intracellular signal transduction
pathways involved in modulating lineage choices remain largely unsolved. Understanding
regulation of these events will allow the development of novel therapeutic
strategies for treatment of disease.
In the development of malignancy it still
remains unclear whether already committed hematopoietic progenitor cells are
targets of oncogenic events, or whether this only occurs in true hematopoietic
stem cells (HSCs). The source of these so-called Leukemic Stem Cells (LSCs) is
critical when considering the success of current therapeutic regimes. Work
within this program aims to understand the processes underlying the development
of leukemia by combining research focused on regulation of normal hematopoiesis
together with a greater understanding of aberrant regulation of hematopoiesis
in LSCs derived from pediatric patients.
Besides investigating the true origin
of the leukemic stem cell it also aims to provide insight into the signal
transduction pathways and transcriptional programs underlying leukomogenesis in
a variety of pediatric disorders.
General Aims
1. Characterization of the molecular
mechanisms regulating HSC fate decisions during both normal hematopoiesis and
development of leukemia.
2. Identification and characterization of
leukemic stem cells in pediatric patients. This will allow the choice for more
intensified therapies at an earlier stage of disease pathogenesis, being more
effective and avoiding ineffective therapy-phases in selected patients.
3. Identification and characterization of
novel genetic translocations and mutations underlying the development of
leukemia and bone marrow failure.
4. To develop and evaluate novel (molecular)
therapies for defective bone marrow function at the pre-clinical and clinical
phase.