Syngeneic and Allogeneic Hematopoietic Stem Cell Transplantation In Mice With Myelodysplastic Syndrome

The myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies characterized by dysplasia, ineffective hematopoiesis and a propensity for progression to acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for the majority of patients. However, overall survival (OS) of patients with MDS following allogeneic HSCT is only about 40%, due to both relapse and non-relapse mortality (NRM) including graft versus host disease (GVHD). Available data suggests that long-term survival following HSCT for MDS is due both to myeloablative therapy and a graft versus tumor (GVT) effect. Mice that express a NUP98-HOXD13 (NHD13) transgene develop MDS with virtually 100% penetrance. In order to develop a pre-clinical model for the study of MDS HSCT, we transplanted NHD13 mice, which are bred on a C57 Bl6 background, with bone marrow harvested from syngeneic C57Bl6 donors. Sub lethally irradiated (650 rad) recipient NHD13 mice transplanted with syngeneic donor cells relapsed early, with no therapeutic benefit in terms of hematologic parameters in peripheral blood or survival. However, lethally irradiated (1000 rad) recipient mice that were transplanted with syngeneic donor bone marrow (BM) showed complete normalization of peripheral blood counts significantly enhanced survival (median survival of 15 months) compared with non-transplanted NHD13 mice (median survival 10 months). Although there were no detectable MDS cells for up to 38 weeks post-transplant, all mice eventually relapsed and died. In order to determine if a GVT effect could enhance survival, we performed 3 types of allogeneic HSCT with donor BM that was mismatched at minor histocompatibility antigen loci (C3H.SW x C57Bl6 donors); donor BM only, donor BM with donor splenocytes (6 x 10E06 CD3+ T cells), and donor BM with donor regulatory T cells (Treg). None of these forms of allogeneic HSCT let to enhanced survival compared to that achieved with syngeneic HSCT. The early relapse rate for allogeneic HSCT with donor BM only was decreased compared to the syngeneic HSCT group (8.3% vs 28% at post-transplantation week 6 and 17% vs 43% at post-transplantation week 16); however, the relapse rate at 38 weeks was similar between the two groups (83.3% vs 85.7%). Adding donor splenocytes, containing reactive T-cells, dramatically decreased the relapse rate, such that the relapse rate was only 20% at post-transplantation week 38, suggesting a GVT effect. This GVT effect was accompanied by a severe GVH effect, and OS was not different between the allogeneic BM + splenocyte and the syngeneic HSCT groups. In an attempt to induce a GVT effect without a severe GVHD, we transplanted allogeneic Treg cells along with allogeneic BM, however, survival and relapse rates were similar to those with allogeneic BM only. Taken together, these findings suggest that a lethal dose of ionizing radiation (1000 rads) is insufficient to eradicate the MDS initiating cell, and that transplantation of donor CD3+ splenocytes leads to decreased relapse rates, but at the cost of severe GVHD. We suggest that the NHD13 mice are a feasible pre-clinical model for the study of HSCT for MDS.