PROJECT SUMMARY/ABSTRACT Therapeutic approaches that harness the immune system to target tumors are revolutionizing the cancer treatment field. Natural Killer (NK) Cells are innate lymphocytes that regulate inflammatory and immune responses and that directly and indirectly kill tumor cells. While NK cell-harnessing immunotherapies have shown great promise as novel treatments for many cancers, NK cells are unable to efficiently kill tumor cells in patients with Myelodysplastic Syndrome (MDS) and related hematological malignancies. This dysfunction impairs immune surveillance, likely contributing to MDS pathogenesis and hindering the efficacy of novel NK cell-harnessing immunotherapies. The molecular and cellular causes of this immune dysfunction have remained enigmatic. In the current proposal, we are investigating the effects of mutations in the spliceosome, which are the most common class of somatically acquired mutations in MDS patients. In preliminary studies, we found that MDS-associated spliceosome mutations drive substantial NK cell dysfunction in mice and humans. Based on these results, we hypothesize that MDS-associated spliceosome mutations impair NK cell function by altering expression or functionality of critical NK cell-intrinsic gene products. We propose to determine the cellular (Aim 1) and molecular (Aim 2) mechanisms underlying these effects. Understanding how the most common class of mutations in MDS patients drives NK cell defects will provide critical mechanistic insights needed to advance development of more targeted and effective immune-based therapies to treat MDS and related malignancies.