Research Report 2010 - MDC

Structure of the GroupFrank RosenbauerGroup LeaderDr. Frank RosenbauerScientistsDr. Andreas EnnsDr. Saeed GhaniDr. Christiane Kuhl*Graduate StudentsAnn-Marie BröskeLena VockentanzJörg SchönheitChiara PerrodMathias Leddin* part of the period reportedTechnical AssistantsVictoria MalchinChristiane Graubmann*Nancy Endruhn*SecretariatSonja GieringPetra HainkCancer, Stem Cells, andTranscription FactorsStem cells are capable of life-long self-renewal and multi-lineage differentiation. Theformation of early progenitors of the myeloid lineage from stem cells is orchestrated bya relatively small number of transcription factors. Among them are PU.1, CCAAT/enhancerbinding protein α (C/EBPα), growth factor independent 1 (GFI1), interferon-regulatory factor8 (IRF8), Runt-related transcription factor 1 (RUNX1) and stem-cell leukemia factor (SCL).Mice in which these genes have been knocked out displayed profound hematopoieticdefects. Moreover, these transcription factors were shown to regulate a broad range ofpivotal target genes, thereby directly programming precursors to differentiate along acomplex developmental pathway. A block in normal differentiation is a major contributingfactor towards the development of solid tumors and leukemias and cells from leukemiapatients frequently harbor mutated or dysregulated transcription factor genes. Thissuggests that altered transcription factor activity is a major driving force behind thepathology of transformation and the development of cancer stem cells.Dynamic PU.1 expression in hematopoiesis andleukemiaOne of the main interests of our laboratory is to understandhow transcription factors direct normal stem cellfunctions, such as self-renewal and differentiation, howthey program precursors to adopt a certain lineagechoice and how disruption of transcription factor activityleads to cancer (stem) cell transformation. Usingboth transgenic and knockout mouse models, we areparticularly interested in discovering crucial molecularup- and downstream mechanisms that regulate theexpression and function of transcription factors. A currentresearch focus in our laboratory is on PU.1. The Etsfamilymember PU.1 is essential for both myeloid andlymphoid lineages. PU.1 knockout mice exhibit earlylethality and lack of B-lymphocytes and mature myeloidcells in fetal livers. In addition, PU.1 is important for HSCself-renewal and differentiation into the earliestmyeloid and lymphoid progenitors. Furthermore, PU.1must be properly downregulated in early thymocytes toallow normal T cell development. It was shown thatgraded changes in PU.1 concentrations have drasticeffects on lineage fate decisions. Therefore, a greaterunderstanding of PU.1 gene regulation is the key todeciphering its role in normal hematopoiesis andmalignant transformation.We identified a novel distal DNA element (termedupstream regulatory element, URE) which is pivotal forproper PU.1 gene expression in vivo. We generated UREdeficient mice (URE ∆/∆ ) using targeted recombination inES cells. Remarkably, URE deletion led to a markeddecrease in PU.1 expression in HSCs, macrophages and Bcells, but an increase in PU.1 expression in early thymocytes.This demonstrated that the URE has an essentialcell context specific regulator function, and directs PU.1expression as an enhancer in myeloid and B-lymphoidcells but functions as a repressor in T cells. Due to theseprofound effects of URE deletion on PU.1 expression,94 Cancer Research