Our recent findings demonstrated that Gli1+ cells are key drivers of bone marrow (BM) fibrosis in the context of primary myelofibrosis (PMF) and that they represent an attractive therapeutic target. We are now in the unique position to dissect mechanisms in the PMF pathogenesis and to discover novel therapeutic strategies for this fatal disease. The specific mechanisms that cause fibrosis and selection of the malignant MPN hematopoietic stem cells (HSCs) over normal HSCs are not completely understood. There is increasing evidence that an altered microenvironment and inflammation play an important role in the progression of primary myelofibrosis (PMF) to a life-threatening condition. We propose that the alarmins S100A8/S100A9 contribute to initiation of BM fibrosis and later to niche-induced genotoxic stress driving loss of normal HSC function, and selection of the MPN clone. Targeting S100A8/S100A9 and downstream targets driving these early events could attenuate BM fibrosis and prevent disease progression and leukemogenesis. We are applying state-of-the-art techniques (genetic-fate-tracing, conditional genetic knockout-mice, CRISPR/Cas9 gene editing and CRISPR-Cas9 whole genome screen) to understand the pathogenesis of disease progression with the ultimate aim to develop targeted therapies with curative intentions.