PROJECT SUMMARY

Current therapeutic strategies for myelodysplastic syndromes (MDS) are unsatisfactory. The development of more effective and better tolerated therapies requires a greater understanding of the molecular basis of MDS. We previously identified mutations in a structure called the spliceosome in patients with MDS. In this project, we are characterizing the role of spliceosome mutations in the development of MDS and asking whether these mutations create specific vulnerabilities in MDS cells that could be exploited therapeutically.

Over the course of the project, we have generated new models for the spliceosome mutations in tissue culture cell lines and genetically-engineered mice. We identified molecular changes in these model systems that faithfully recapitulate what we see in patient samples with these mutations. We have also demonstrated that mice carrying these mutations have abnormalities in blood development similar to MDS patients, but these mice do not spontaneously develop MDS. In ongoing work, we are refining these mouse models further to create full-blown MDS so that we can use them to improve our understanding of the molecular basis of MDS and test new therapies. Finally, we took advantage of a new tool that allows us to disrupt every gene in the human genome and applied this to cells with spliceosome mutations. We have interesting results from these experiments that have uncovered vulnerabilities that may point us towards novel strategies for treating MDS patients.

Overall, we are pleased with the progress made over the course of the project and are extremely grateful for the critical support provided by the Evans Foundation.