Modeling Defective Erythropoiesis in Myelodysplastic Syndrome (MDS)

Abstract

Anemia is a significant clinical component of MDS, which results from defective erythropoiesis. By 30 weeks of age, a murine model of MDS based on genetic defects in Nup98-HOXD13 (NHD13) recapitulates the peripheral cytopenias seen in patients, including macrocytic anemia (Balderman et al. 2016, Blood 127:616). We found that these defects in the peripheral blood were correlated with decreases in marrow erythropoiesis at the earliest erythroid-specific progenitor (BFU-E), as well as a decrease in the expansion of downstream erythroblast precursors. Along with a cell-intrinsic defect, erythropoiesis in MDS patients could also be influenced by bone marrow microenvironmental changes. To investigate potential cell-intrinsic and microenvironmental defects, we analyzed erythropoiesis in chimeric mice transplanted with both UBC-GFP+ wildtype bone marrow and either 1) cells from NHD13, or 2) another MDS model based on overexpression of Evi1, or 3) unlabeled wildtype cells, which served as controls. In the two chimeric MDS models, cytopenias were not observed until after 15 weeks post-transplantation. Yet as early as 6 weeks post-transplant, analysis of peripheral blood demonstrated that GFP+ wild-type cells contributed disproportionately to circulating red blood cell (RBCs) in both MDS models. In the bone marrow of chimeric mice with normal hematocrits, we found significant decreases in both MDS-derived and wildtype BFU-E. The maintenance of RBC numbers was achieved by extensive expansion of wildtype erythroid precursors. Concurrently, MDS-derived erythroid precursors failed to expand, as seen in the non-chimeric NHD13 model. At later time-points when cytopenias become evident in the periphery of the chimeric MDS mice, erythropoiesis was still provided by wildtype cells, but the bone marrow intermediates were no longer present in sufficient numbers to prevent anemia. The source(s) of this cell-extrinsic inhibition of erythropoiesis during MDS progression may include the expanding myeloid cell populations derived from the MDS clone, which we found both in the non-chimeric NHD13 model, as well as in both chimeric MDS models. Taken together, these data suggest that MDS leads to an intrinsic block in erythropoiesis and to a progressive expansion of myelopoiesis in the marrow. These changes initially lead to a compensatory increase in erythropoiesis from wild-type cells to preserve normal RBC output, which ultimately fails with continued disease progression. DisclosuresNo relevant conflicts of interest to declare.