PLX254998

GSE107490: TGF1-mediated functional inhibition of mesenchymal stromal cells in MDS and AML

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Mesenchymal stromal cells (MSC) are involved in the pathogenesis of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), but how they contribute to the expansion of malignant cells and hematopoietic failure is poorly understood. To further characterize the pathological phenotype we performed RNA sequencing of MSC from patients with MDS and AML. Data analysis revealed a specific molecular signature with a significant overlap of genes commonly deregulated in all MDS subtypes and in AML. Pathway analysis revealed a strong enrichment of genes related to osteogenesis, senescence, inflammatory processes and inhibitory cytokines thereby reflecting the structural and functional deficits of MDS- and AML-derived MSC on a molecular level. Further analysis identified TGF1 as the most probable extrinsic trigger factor for this altered gene expression. Following exposure to TGF1 healthy MSC adopted a phenotype reminiscent of that observed in primary patient-derived MSC which was characterized by impaired growth potential, osteogenic differentiation capacities, a specific gene expression profile and diminished stromal hematopoietic support. These suppressive effects of TGF1 on MSC functionality were abrogated by SD-208, an established inhibitor of TGF receptor signalling. Blockade of TGF signalling by SD-208 also restored the osteogenic differentiation capacity of patient-derived MSC, thus confirming the role of TGF1 in the bone marrow microenvironment of patients with MDS and AML. Our findings establish TGF1 as a relevant trigger causing functional inhibition of MSC in MDS and AML and identify SD-208 as a candidate for the reversal of these effects SOURCE: Thomas Schroeder (Thomas.Schroeder@med.uni-duesseldorf.de) - University of Duesseldorf, Medical Faculty