In this study, circulating S100A8 and S100A9 homodimers and S100A8/A9 heterodimers in plasma were systematically investigated by ELISA in aplastic anemia (AA) and myelodysplastic syndromes (MDS).
Here we report an increased expression of PD-1 on HSPCs and PD-L1 on MDSCs in MDS versus healthy donors, and that this checkpoint is also activated in S100A9 transgenic (S100A9Tg) mice, and by treatment of BM mononuclear cells (BM-MNC) with S100A9.
In particular, CD33 is strongly expressed in MDSC isolated from patients with MDS where it has an important role in MDSC-mediated hematopoietic suppressive function through its activation by S100A9.
Our data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.
In view of the relationship between the early stage of myelodysplastic syndrome and the immune system, we hypothesize that the expression of the S100a8 and S100a9 genes is a feature that can be used for diagnosis during the early stage of the myelodysplastic syndrome and that the 2 genes could be used as targets in treating this disease.
These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.