Kurzfassung

With aging, the number of somatic mutations in the hematopoietic compartment constantly increases, leading to a progressive loss of polyclonal hematopoiesis and the evolution of a pre-malignant condition termed clonal hematopoiesis of indeterminate potential (CHIP). In some patients, CHIP progresses towards stem cell driven neoplasms such as myelodysplastic syndromes (MDS). However, the precise mechanisms that drive this process have not been defined. Moreover, an essential role of the...With aging, the number of somatic mutations in the hematopoietic compartment constantly increases, leading to a progressive loss of polyclonal hematopoiesis and the evolution of a pre-malignant condition termed clonal hematopoiesis of indeterminate potential (CHIP). In some patients, CHIP progresses towards stem cell driven neoplasms such as myelodysplastic syndromes (MDS). However, the precise mechanisms that drive this process have not been defined. Moreover, an essential role of the osteo-hematopoietic niche in MDS propagation has been reported. Alterations of the mutual crosstalk within this microenvironment specifically contribute to the age-associated manifestation of MDS and subsequent progression into acute myeloid leukemia (AML), thereby supporting the concept of niche mediated leukemogenesis. Mesenchymal stromal cells (MSCs) and endothelial cells represent the major stromal populations of the BM niche that are important for the functional maintenance of healthy HSC but also play a supportive role for cancer stem cells (CSC) emergence and progression toward MDS/AML. However, we still lack knowledge of these complex CSC-niche interactions and their dynamic adaptation may be best captured in a model that enables quantitative evaluation and prediction to reveal the most relevant BM niche elements and their impact on CHIP/MDS/AML pathogenesis. In collaboration with clinical teams in Dresden and Munich along with access to BM biobank from the CHOICE DKTK Consortium (BoHemE study, NCT02867085), our lab will study the stromal profiles and molecular alterations present in MSC and endothelial populations from CHIP/MDS patients. Specifically, our group aims to characterize of the cellular components of the osteo-hematopoietic niche in trephine BM core biopsies from CHIP and MDS clinical cases compared to healthy individuals. We will also aim to identify distinctive MSC/endothelial cell niche profiles that will be correlated to the clinical characteristics of the CHIP/MDS patients and evaluated regarding their prognostic value for disease progression and/or survival prediction. Subsequently, the CHOICE consortium will comprehensively analyze how specific cellular and molecular pathways within the aging osteo-hematopoietic niche contribute to the pathogenesis and differential progression of CHIP and MDS.» weiterlesen» einklappen