High BM plasma S100A8/A9 is associated with a perturbed microenvironment and poor prognosis in myelodysplastic syndromes.

S100A8/A9 is a proinflammatory protein and plays an essential role in the pathogenesis of myelodysplastic syndromes (MDS) via the S100A8/A9-Toll-like receptors axis. While S100A8/A9 levels have been used as biomarkers in many inflammatory diseases, their clinical relevance has not been conclusively resolved in MDS. To address this, we used an enzyme-linked immunosorbent assay to quantify S100A8/A9 heterodimers in bone marrow (BM) plasma from 215 MDS patients and compared S100A8/A9 levels across patients with various disease risks and genotypes. S100A8/A9 levels correlated with ASXL1 variant allele frequencies significantly. Moreover, mutant ASXL1 with concurrent RUNX1, STAG2, ZRSR2, or EZH2 mutations was associated with higher S100A8/A9 levels. We further showed that higher S100A8/A9 independently predicted inferior leukemia-free survival and overall survival in MDS patients, irrespective of age, Revised International Prognostic Scoring System subgroups, and known detrimental mutations. Lastly, through deep-sequenced transcriptomic analysis, we demonstrated that higher S100A8/A9 in the BM intimated a perturbed microenvironment with enhanced myeloid-derived suppressor cell-mediated tumor immune escape signal, altered metabolism, and impairment in the functions and quantities of CD8+ T cells and NK cells. S100A8/A9 in the BM microenvironment may be a potential biomarker in the prognostication of MDS and target for novel therapy.