Hematopoiesis entails the generation of stem cells, the proliferation and maintenance of multipotential progenitors,
lineage commitment and maturation. The regulation of these different cell fates is complex and poorly understood.
Deregulation of these processes can lead to the formation of malignancies such as cancer.
This project aims to understand blood cell production by studying an essential player in blood cell development,
the proto-oncogene PU.1 gene. PU.1 deficient mice have revealed an essential role of the gene in early
hematopoietic stem/progenitor cells as PU.1 -/- mice lack all types of blood cells. PU.1 is, however, expressed at
multiple stages of the differentiation of several lineages. The role of PU.1 in later developmental stages is mainly
unknown due to the early lethality of PU.1 -/- mice. To study PU.1 during these later phases a mouse model will be
used that allows tissue and time specific deletion of the gene. The project includes: 1) The determination of PU.1
expression pattern during lymphoid development. 2) The conditional inactivation of PU.1 in different lymphoid
lineages at different developmental time points and subsequent analysis of the consequences of the loss of the gene
function using a combination of multi-parameter flow cytometry and a variety of in vitro cell biological assays. 3)
The specific deletion of this transcription factor will further enable, for the first time, the testing of PU.1 targets for
their reliance on PU.1 in a genetic system.
We expect that knowledge of normal cellular differentiation will then facilitate the development of therapeutic
interventions when these transcriptional pathways are inappropriately activated during cancer.