To dissect the role of the alarmins S100A8/S100A9 in bone marrow fibrosis and clonal evolution in myeloproliferative neoplasms

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Primary myelofibrosis (PMF) is the most aggressive subtype of myeloproliferative neoplasms (MPNs) and the prototypic example of bone marrow (BM) fibrosis. In this condition, the hematopoietic marrow is incrementally replaced by scar tissue ultimately resulting in bone marrow failure. To this date, allogenic stem cell transplantation is considered the only therapeutic op-tion with curative intentions, which itself is associated with high rates of mortality and morbidity.There is increasing evidence that an altered microenvironment and inflammatory processes play an important role in the progression of the disease to a life-threatening condition, including leukemic transformation. The specific mechanisms that cause fibrosis and selection of the malignant MPN hematopoietic stem cells (HSCs) over normal HSCs are only incompletely understood, especially since the fibrosis-driving cells have remained obscure. The lack of a deeper pathophysiological understanding of disease progression limits pharmacological targeted therapy. Recent findings in the Schneider lab demonstrate that Gli1+ cells are key drivers of BM fibrosis and that they represent an attractive therapeutic target. This puts me in the unique position to dissect mechanisms in the PMF pathogenesis and to discover novel therapeutic possibilities for this fatal disease. Based on preliminary work in the Schneider and Raaijmakers lab, I propose that the alarmins S100A8/S100A9 contribute to initiation of BM fibrosis and during progression to niche-induced genotoxic stress driving the loss of normal HSC function, and selection of the MPN clone over normal hematopoieisis. Targeting S100A8/S100A9 and downstream targets mediating these early events could attenuate BM fibrosis and prevent disease progression and leukemogenesis.I will apply state-of-the-art techniques (genetic-fate-tracing, conditional genetic knockout-mice, CRISPR/Cas9 gene editing) and will validate our findings in patient samples with the ultimate goal to optimize the diagnosis of pre-fibrotic states of PMF and to develop novel therapeutic strategies with curative intentions.