A Shared Sf3b1 Neoantigen Is Presented On Primary Malignant Cells And Induced Pluripotent Stem Cell-Derived Hematopoietic Lines

Myeloid malignancies are susceptible to immunologic destruction but antigen-specific T cell immunotherapies for these diseases are currently limited. Immunotherapies targeting neoantigens created from recurrent protein-coding mutations should selectively eradicate malignant cells and spare their normal counterparts to limit the risk of myeloablation. In particular, the paucity of neoplastic cells in MDS specimens impedes the identification and validation of targetable neoantigens for the development of immunotherapies for this disorder. Induced pluripotent stem cells (iPSC), generated from primary patient cells and differentiated into hematopoietic lines, can recapitulate the genotype and phenotype of the original disease (Hsu et al., Blood 2019) and could provide a renewable source of MDS progenitor cells for the development of novel T cell immunotherapy. SF3B1 mutations serve as a neoplastic driver for myeloid neoplasms (Papaemmanuil et al., Blood 2013), occuring in 20-30% of all MDS and >60% of MDS with ringed sideroblasts (Cazzola et al., Blood 2013). We hypothesized that SF3B1 mutations produce HLA-presented neoantigens, which can be targeted to eliminate primary MDS cells and iPSC with SF3B1 mutations.