PROJECT SUMMARY

Myelodysplastic syndromes (MDS) are among the most common hematologic malignancies, but there are few suitable therapeutic options. There are challenges in studying the biology of the disease, which lacks a model system that replicates the microenvironment that is required to propagate the diseased state. To identify new therapeutic approaches for MDS patients, we must improve the ability to evaluate MDS patient cells in the laboratory. To do this, it is critical to create models that can mimic structure or function of the human bone marrow. The conventional approaches that involve culturing cells over a monolayer of bone marrow (BM) stroma cells [e.g. two-ˇdimensional (2D)] are not able to replicate many of the intricacies of the BM niche that supports the growth of MDS. Our hypothesis is that a culture system capable of recapitulating key BM niche conditions will better maintain MDS cells, allow for the better understanding of how the disease progresses, and result in the discovery of novel therapeutic approaches. We have established a novel 3D spheroid co-ˇculture system that can duplicate key features that exist in the BM niche. Using cells from leukemia patients, we have demonstrated that leukemia cells are better maintained and retain functional properties using the 3D stromal approach compared to more conventional culture systems. Our preliminary experiments indicate this approach will also be successful in MDS. To that end, we propose to evaluate MDS cells to determine their survival dependencies in the context of niche interactions. The short-ˇterm goal is to provide a novel methodology and resource that allows MDS investigators to study MDS patient samples in the laboratory. The ultimate goal is to leverage this system to identify new therapeutic approaches for MDS either directly or through disruption of the protective interactions between the bone marrow and the MDS cells.