RHOT2 mutant peptide–HLA class I complex (RHOT2-HLA complex)

The RHOT2 mutant peptide–HLA class I complex is a tumor-specific neoantigen target primarily identified in myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This complex arises from recurrent RNA mis-splicing events, such as intron retention, which are triggered by neomorphic mutations in splicing factors like SRSF2 or ZRSR2. These splicing alterations lead to the translation of frame-shifted, immunogenic peptides from the RHOT2 (Ras Homolog Family Member T2, also known as Miro2) gene. These mutant peptides are subsequently processed and presented on the cell surface by the HLA-A*02:01 molecule, where they can be recognized by the adaptive immune system. Because these splicing mutations are highly stereotyped across different patients, the RHOT2-HLA complex serves as a "public" neoantigen, making it a promising candidate for off-the-shelf immunotherapy. Therapeutic development focuses on T cell receptor-engineered T (TCR-T) cells designed to specifically recognize this complex and induce the lysis of leukemic cells while sparing healthy tissues that do not harbor the splicing mutations.

Other names

Miro2 mutant peptide–HLA complexRHOT2 neoantigenSRSF2-mutant induced RHOT2 neoantigenRHOT2-HLA-A*02:01 complexRas homolog family member T2 mutant peptide–HLA complex

T cell receptor (TCR) mediated recognition of the mutant peptide-HLA complex leading to cytotoxic T lymphocyte (CTL) activation and selective lysis of the target cell.