Myelodysplastic syndrome (MDS) is a malignant condition of the bone marrow that frequently leads to anemia and death. Despite the introduction of new therapies, the only curative therapy to date remains stem cell transplantation, which is only available for a minority of patients. Notably, cellular and immunotherapies are increasingly emerging as front-line treatments for cancer. However, this strategy requires knowledge of targets for the immune system to attack. For MDS patients, these targets have remained unknown. We propose to fill this gap in knowledge, to pave the way for future efforts to harness cellular and immunotherapies for MDS.

Using cutting edge genomics and computational techniques, we have deeply probed the universe of mRNA isoforms present in MDS samples and matching controls. This work establishes the alternative splicing of genes as a dominant source of new cell surface markers in MDS. Such proteins represent common targets for the development of new immune therapies. In this grant, we will use cutting edge single-cell genomics technologies to reveal the precise cellular and genetic origins of these immune targets and alterations to the mRNA machinery that govern their production. To lead the way toward efforts in the clinic, we will validate the cellular localization and expression of these targets in patient bone marrow. We expect this work to serve as a launching pad for the development of new diagnostics and broad reaching immune therapies in MDS.