Although suspected to be of critical relevance to MDS pathogenesis, little is known about how alterations in MDS-associated niche cells (e.g. Mesenchymal stem progenitor cells, Endothelial cells, Macrophages, etc.) contribute and support the disease phenotype, and which molecular mechanisms are at play. By working closely with clinical collaborators, and using patient-derived materials, we explored molecular changes that are preferentially seen in MDS-associated niche cells compared to age-matched control donors. In doing so, we identified alterations that we hypothesized could have biological significance in MDS. With the support of the ERC funding, we were able to develop the necessary tools and model systems (Tirado-Gonzalez and Czlonka, 2018, Leukemia and unpublished) to explore the biological significance of these changes in experimental models that are of relevance to the human disease. Our findings indicate the co-existence of both direct and indirect mechanisms by which niche cells promote MDS expansion. For instance, we discovered a factor, produced by several niche cells in the MDS microenvironment (macrophages and MSCs) that supports MDS progression both directly, by acting as a growth factor on malignant cells and indirectly by negatively impacting the immune micromilieu, and ultimately enabling MDS/sAML cells to evade immune control (Tirado-Gonzalez and Descot, 2021, Cancer Discovery). These results were widely disseminated to the scientific community through presentations at highly visible international meetings (Several International MDS Symposiums; annual meeting of the American Society of Hematology, annual meeting of the American Association for Cancer Research, etc.) but also exploited, in collaboration with industrial partners, to support a clinical trial, which outcome could have direct impact on patients suffering from MDS/sAML. Besides these major achievements, knowledge and tools from this ERC action have spurred the development of new research lines in our laboratory, as well as new scientific collaborations with colleagues from and outside the life-sciences.
