An MDS xenograft model utilizing a patient-derived cell line

Animal models that faithfully recapitulate clinical features of myelodysplastic syndrome (MDS) have been difficult to establish. MDS are hematologic disorders associated with ineffective hematopoiesis, blood cytopenias, myeloid dysplasia and an increased risk of acute myeloid leukemia (AML). Although transplantation of primary AML cells into immunocompromised mice has been met with much success, primary MDS patient samples exhibit poor engraftment with no evidence of disease in recipient animals.1–3 The engraftment of primary MDS samples is complicated further by frequent outgrowth of normal HSC clones.4 These challenges underscore the current limitations and inefficiencies of engrafting primary MDS cells. Recent improvements in engrafting primary MDS cells have been observed when transplanting immunophenotypically defined HSC from the marrow of MDS patients or when co-injecting stromal cells engineered to produce non-cross-reacting human cytokines.5,6 Unfortunately, even with the improved engraftment of primary MDS cells, mice do not succumb to features resembling human MDS, precluding the use of these models for pre-clinical testing. To circumvent the current limitations, we developed a model using immunocompromised recipient mice and a human MDS cell line (MDSL) derived from the non-leukemic phase of an MDS patient with refractory anemia-ringed sideroblasts.7–9 The MDSL line was derived as a subline of MDS92, and maintains factor dependency for cell growth, but has reduced differentiational capacity compared with MDS92.10 Herein, we report the successful engraftment of MDSL cells into NOD/SCID-IL2Rγ mice (NSG) and NSG-hSCF/hGM-CSF/hIL3 (NSGS) mice, and reproducible development of disease, including cytopenias, clonal expansion and host hematopoietic suppression. In addition, we show that the MDSL xenograft model is a useful tool for evaluating novel and existing therapeutics for MDS.