PROJECT SUMMARY

New therapies for patients with cancer who have relapsed after standard treatment is an urgent unmet need. Alterations of the nuclear export protein XPO1 in cancer include mutations and overexpression, and are particularly seen in blood cancers. We have previously observed high expression of XPO1 in patients with acute myeloid leukemia and myelodysplastic syndromes (MDS) that is associated with worse outcomes. Targeted therapies that selectively inhibit XPO1 are approved for use in related blood cancers such as multiple myeloma and lymphoma but have not yet successfully been developed in leukemia and MDS. Furthermore, animal models and detailed mechanism of action studies are lacking, potentially slowing the translation towards new clinical therapies and combination therapies for patients. To address these problems, we will also investigate whether XPO1 inhibition perturbs RNA export and how that affects gene expression, splicing, and translation given the known role of XPO1 to export certain messenger RNA, small nuclear RNA, and ribosomal RNA species via RNA-binding proteins. Lastly, we will use our models to test potential targets for combination with XPO1 inhibition in an unbiased manner. This proposal can be expected to have a direct and significant positive impact on the field of precision medicine in MDS.