In our projects we hypothesize that ALL cells display active mechanisms mediating growth arrest and survival upon chemotherapy and in response to different niches (e. g. bone marrow and central nervous system). We also hypothesize that populations of leukemia-initiating cells contribute to residual disease through adaptive survival strategies rendering them quiescent and therapy-resistant. Finally, we propose to test new strategies to sensitize residual leukemic cells to novel and established therapeutic strategies.
We are working with conventional and unconventional xenograft models for ALL cells, allowing studies on homing and engraftment of leukemic cells into different microenvironments, in vivo drug testing and longitudinal in vivo imaging. We identified p38SAPKα/β as a major mediator of ALL cell growth in permissive in vivo microenvironments and p38α/β inhibition as a means of abrogating this response and prolonging survival in experimental animal models.
Analogous to the situation in DTCs, we are also working on identifying a role for TGFβ1/2 signaling in mediating dormancy of ALL cells in vitro and in the bone marrow microenvironment in vivo. We established a strategy to longitudinally monitor the course of patient ALLs by longitudinal engraftments of different disease stages in immunodeficient mice. These stages include initial diagnosis, residual disease and relapse.
We are also establishing strategies to identify leukemia-initiating populations in patients whose leukemias cannot be correctly identified as high-risk by conventional strategies. With our cooperation partners within the ALL-BFM study group and others we are also interested in large-scale analysis of markers relevant to dormancy in residual disease.