Here we report a novel role for the PD-1/PD-L1 pathway in MDS beyond the regulation of T-cell biology, whereby aberrant activation of PD-1 on HSPCs by MDSC-derived PD-L1 triggers hematopoietic cell death, contributes to BM failure, and suppresses hematopoiesis. Here, CD274 is linked to myelodysplastic syndrome.