Research interests

Over the last decade we have specifically been interested in the clonal composition of post-transplant hematopoiesis and genotoxicity in connection with retroviral vector integration both in preclinical animal models as well as clinical gene therapy studies. By means of a highly innovative methodology for the identification of individual integration sites of viral vectors which we developed it was possible for the first time to thoroughly investigate retroviral integration in numerous gene therapy studies. In clinical as well as preclinical gene transfer studies the clonal composition of early and late hematopoiesis after transplantation could be elucidated. We could show on the molecular level that with increasing efficiency of clinical gene therapy trials the risk of side effects raises, ranging from subtle to clonal dominance or even oncogenesis. We have shown that the vectors used for gene therapy tend to integrate into regions of the genome of target cells affecting stem cell survival and proliferation. Thus, highly sensitive insertional mutagenesis analysis has proven to be an efficient tool for the screening of genes affecting stem cell growth with oncogenic potential in humans. For the future, we will intensify our research aiming at an improved biosafety by evaluating related assays for onco and retroviral gene transfer. We also aim to prospectively monitor insertional mutagenic events in real-time. Simultaneous analysis of integration sites at the DNA level and individual and global gene expression pattern on single cell derived colonies will allow to identify regulatory events of functional mechanisms underlying clone selection.

Another area of interest of our group is the structure of the transplantable human hematopoietic stem cell compartment in xenotransplantation models. We have extensive experience with various syngeneic as well as xenogeneic mouse stem cell transplantation models. We were able to establish a xenotransplantation model that for the first time revealed functional heterogeneity of human hematopoietic stem cells and the role of human short-term repopulating cells (STRC). Moreover, using techniques that allow the isolation of viable hematopoietic cells in specific stages of the cell cycles or in accordance with their cell cycle history in culture we were able to directly prove the self-renewal activity of human repopulating cells in culture and demonstrate cell cycle-related changes in the transplantability of stem cells. Our human colon carcinoma xenotransplantation model will enable us to evaluate the contribution of individual clones for self renewal capacity, tumor progression and metastasis.

• Hematology and Oncology
• Retrovirology
• Molecular and gene therapy for cancer and inherited diseases
• Short and long term hematopoiesis