Recent advances in understanding of the immune system have led to a major breakthrough in cancer therapy, with the development of drugs that target the immune system rather than the cancer cells. Mature T-cells express a T-cell receptor (TCR) that binds to antigen presentation machinery (APM) on the surface of other cells; this interaction allows for T-cell activation. Antigen presentation machinery includes MHC-I that allows for communication with cytotoxic CD8 T-cells and MHC-II which allows for communication with CD4 helper T-cells. Many cancers and pre-cancerous conditions, including MDS (and MDS-induced AML), are associated with a downregulation of APM that may enable immune evasion and is an important prognostic factor for the efficacy of immunotherapies. Currently, established immunotherapies have yielded modest results in MDS/AML, and they are not offered to patients. This project will build on our recently published work that established that two membrane proteins and a E3-ubiqutuin ligase, SUSD6, TMEM127, and WWP2 (STW), act together to suppress surface expression of MHC-I in AML and solid cancers. Our data suggests that the STW complex is variably expressed in malignant MDS cells and its expression increases over the course of the malignant transformation to AML. Our project will further characterize how this complex comes together and how it might be targeted in MDS, hopefully opening the way for future clinical trials.