Loss of PDL1 in mesenchymal stromal cells from young-onset MDS-RAEB-1 promotes inflamm-aging through epigenetic dysregulation of H3K9me3

Myelodysplastic syndromes (MDS), an age-related hematological malignancy, involve dysfunctional bone marrow mesenchymal stromal cells (BM-MSCs). Our study reveals that BM-MSCs from young refractory anemia with excess of blasts-1 (RAEB-1)/MDS patients exhibit impaired proliferation, altered immunophenotype, and reduced immunosuppressive capacity compared to healthy donor (HD)-MSCs. Notably, MDS-MSCs display a senescent state, distinct morphology, and elevated secretion of senescence-associated secretory phenotype (SASP) cytokines. Mechanistically, loss of programmed cell death ligand 1 (PDL1) in MDS-MSCs correlates with decreased SETDB1 levels and reduced H3K9me3-marked heterochromatin, leading to a more open chromatin state. This SETDB1/H3K9me3 deficiency mediates the reduction in immunosuppressive function and the increase in SASP factors (e.g. IL-6, IL-8, MCP1), exacerbating inflamm-aging. Gene expression profiling showed stage-specific senescence and inflammation phenotypes across MDS-MSCs generations. Furthermore, H3K9me3 inhibition directly induced BM-MSC senescence. Our findings demonstrate that dysfunctional BM-MSCs, driven by PDL1-SETDB1-H3K9me3 axis disruption and consequent SASP, critically promote pathogenesis in young MDS-RAEB-1 patients.