SP 2 - Fibromap
Dissecting myofibroblast activation and cross-talk in bone marrow fibrosis
Bone marrow (BM) fibrosis is the continuous replacement of blood forming cells in the BM by excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Primary myelofibrosis (PMF) is an incurable blood cancer and the prototypic example of progressive development of BM fibrosis. The cause of PMF is largely unknown, but is associated in the majority of cases with a JAK2(V617F) mutation in hematopoietic cells. A better understanding of the step-wise pathogenesis of bone marrow fibrosis is crucial for the diagnosis of a pre-fibrotic state, which allows an early intervention, as established fibrosis is non-reversible. So far, the cells, which drive BM fibrosis, have remained obscure, impeding the cellular and molecular dissection of this process. We just demonstrated that the nuclear protein and transcription factor Gli1 marks the critical effector cells in BM fibrosis and that these Gli1+ stromal cells are a highly attractive therapeutic target (Schneider , Cell Stem Cell, 2017). Our results offer a novel entry point for future research and are of central importance for this proposal. One major focus of our proposal will be to understand the stepwise progression of bone marrow fibrosis associated with blood cancer by dissecting the interaction of blood forming cells with fibrosis-driving cells. We will apply single cell RNA- and ATAC-sequencing to determine cellular players and mechanisms involved in this fibrotic transformation. It is the ultimate goal of this proposal to identify novel biomarkers and therapeutic targets for this so far incurable disease