Research
AG Rosenbauer main projects:
Stem cells & leukemia
DNA methylation and cancer
Recent progress in isolation, investigation, and manipulation of stem and progenitor cellshas boosted the role of the hematopoietic system as a model to understand basic paradigmsunderlying cell differentiation and maturation. The mechanisms that govern hematopoieticstem cell activity and lineage specification are increasingly well known, and it could clearlybe demonstrated that errors in pathways controlling these functions are a major drivingforce in malignant transformation. Moreover, investigation of hematopoietic stem cellbiology has changed the view on cancer, and it is now believed that tumors are sustained bycancer stem cells, a highly malignant subpopulation which maintains the uncontrolledproduction of less malignant daughter cells. It is therefore essential to identify those pathways that control key stem cell functions in order to better understand the genes involved in transformation, tumor progression and relapse. Although tightly controlled epigenetic chromatin modifications such as DNA-methylation are believed to affect cellular development, their precise role during distinct cellular differentiation stages such as stem- and progenitor cells is poorly known. Here, we propose to analyze in detail the developmentof the hematopoietic lineages in mice with engineered regulatable increased or decreased DNA methyltransferase 1 (DNMT1) expression, the major enzyme for maintaining proper DNA methylation during cell divisions. In particular, we will address how DNMT1 controls important hematopoietic stem cell properties such as self-renewal, and orchestrates critical lineage development decisions of differentiating blood precursors.
Genregulation
Transcription factors orchestrate hematopoietic development
The hematopoietic system is an ideal model in which to study tissue development from normal stem cells and the formation of neoplasms (leukemias and lymphomas) from cancer stem cells. Differentiation of hematopoietic stem cells (HSCs) and progenitors is under strict control of a regulatory network orchestrated by lineage-specific transcription factors. Among the best-studied examples are PU.1, CCAAT/enhancer-binding protein α(C/EBPα), AML-1, GATA-1, c-myb, SCL/Tal-1, and IRF-8. Mice in which these genes have been knocked out display profound hematopoietic defects. Moreover, these transcription factors have been 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 toward 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.
MicroRNAs in hematopoiesis and leukemia
Function of microRNAs in myeloid differentiation