The bone marrow stroma in human myelodysplastic syndrome reveals alterations that regulate disease progression.

Overview

Myelodysplastic syndromes (MDS) are a heterogenous group of diseases affecting the hematopoietic stem cell that are curable only by stem cell transplantation. Both hematopoietic cell intrinsic changes and extrinsic signals from the bone marrow (BM) niche seem to ultimately lead to MDS. Animal models of MDS indicate that alterations in specific mesenchymal progenitor subsets in the BM microenvironment can induce or select for abnormal hematopoietic cells. Here we identify a subset of human BM mesenchymal cells marked by the expression of CD271, CD146 and CD106. This subset of human mesenchymal cells is comparable to mouse mesenchymal cells that, when perturbed, result in an MDS-like syndrome. Transcriptional analysis of them identified Osteopontin (SPP1) as the most overexpressed gene. Selective depletion of Spp1 in the microenvironment of the mouse MDS model, Vav-driven Nup98-HoxD13, resulted in an accelerated progression as demonstrated by increased chimerism, higher mutant myeloid cell burden and a more pronounced anemia when compared with wild type microenvironment controls. These data indicate that molecular perturbations can occur in specific BM mesenchymal subsets of MDS patients. However, the niche adaptations to dysplastic clones include Spp1 overexpression that can constrain disease fitness and potentially progression. Therefore, niche changes with malignant disease can also serve to protect the host.