Rebekka K. Schneider, MD

Project Titile: Functional and molecular dissection of the fibrotic transformation and clonal selection in myeloproliferative neoplasms

Primary myelofibrosis (PMF) is an incurable subtype of myeloproliferative neoplasms (MPN) and the prototypic example of bone marrow (BM) fibrosis. There is increasing evidence that the altered microenvironment and inflammation play an important role in the progression to a life-threatening condition. The specific mechanisms that cause fibrosis and selection of the malignant MPN hematopoietic stem cells (HSCs) over normal HSCs are not completely understood, in particular as the fibrosis-driving cells have remained obscure.

Our recent findings demonstrate that Gli1+ cells are key drivers of BM fibrosis 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.

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 S100A/S100A9 and downstream targets driving these early events could attenuate BM fibrosis and prevent disease progression and leukemogenesis.

We 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 aim to develop targeted therapies with curative intentions.

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