Overlapping Stromal Alterations in Myeloid and Lymphoid Neoplasms.

Simple Summary: Simple Summary: Myeloid and lymphoid malignant cells can become the dominant population in the bone marrow and thus inhibit healthy hematopoiesis. Patients suffer enormously as a result. In addition to the directly mediated inhibition of healthy hematopoietic stem and progenitor cells, indirect mechanisms via so-called mesenchymal stromal cells can also play a role. We are focusing our research on the latter and would like to identify functional and molecular overlapping mechanisms within the various myeloid and lymphoid neoplasms. In the future, it may be possible to block these mechanisms and thus prevent disease progression or improve healthy hematopoiesis. Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic insufficiency. The mechanisms by which clonal malignant cells inhibit normal hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) have not been unraveled so far. Given the pivotal role of mesenchymal stromal cells (MSCs) in the regulation of hematopoiesis in the BM niche it is assumed that MSCs also play a relevant role in the pathogenesis of hematological neoplasms. We aimed to identify overlapping mechanisms in MSCs derived from myeloid and lymphoid neoplasms contributing to disease progression and suppression of HSPCs to develop interventions that target these mechanisms. MSCs derived from healthy donors (n = 44) and patients diagnosed with myeloproliferative neoplasia (n = 11), myelodysplastic syndromes (n = 16), or acute myeloid leukemia (n = 25) and B-Non-Hodgkin lymphoma (n = 9) with BM infiltration and acute lymphoblastic leukemia (n = 9) were analyzed for their functionality and by RNA sequencing. A reduced growth and differentiation capacity of MSCs was found in all entities. RNA sequencing distinguished both groups but clearly showed overlapping differentially expressed genes, including major players in the BMP/TGF and WNT-signaling pathway which are crucial for growth, osteogenesis, and hematopoiesis. Functional alterations in healthy MSCs were inducible by exposure to supernatants from malignant cells, implicating the involvement of these factors in disease progression. Overall, we were able to identify overlapping factors that pose potential future therapeutic targets. [ABSTRACT FROM AUTHOR]