Instructive Interaction between Myelodysplastic Hematopoiesis and the Bone Marrow Microenvironment at Single Cell Level

Myelodysplastic Neoplasms (MDS) are hypothesized to re-model their bone marrow (BM) microenvironment to reinforce conditions for their propagation. In this study, we investigated interactions between MDS cells and the BM niche at single cell level. In a patient-derived xenograft (PDX) model, we analyzed 13,000 cells of different murine niche cell populations after long-term (>24 weeks) exposure to MDS versus healthy human grafts. Subsequently, we analyzed over 24,000 primary human BM cells enriched for the non-hematopoietic compartment by using whole bone fragments from n=8 MDS patients and n=7 healthy age-matched donors. In MDS transplanted PDX, mesenchymal cell (MSC) subpopulations were forced to overexpress hematopoietic factors such as Cxcl12 and Il7 upon contact with hematopoietic MDS cells as compared to healthy grafts. Single cell analyses of primary in situ BM cells from MDS patients showed highly heterogeneous MSC subpopulations on a patient-individual level. We identified inflammatory gene expression profiles as well as overexpression of CXCL12, KITLG and IL7 in MDS MSCs and endothelial cells. In conclusion, we demonstrate re-programming of the BM microenvironment by MDS cells pointing to altered MSC subpopulations with increased growth factor expression profiles in a subgroup of MDS patients.