Mutant nucleophosmin 1-derived peptide-HLA class I complex (Mutant NPM1-HLA complex)

Mutant Nucleophosmin 1 (NPM1) is a hallmark genetic alteration found in approximately 30% of adult patients with acute myeloid leukemia (AML) (Falini et al., 2005, NEJM). The mutation, typically a four-base pair insertion in exon 12, results in a frameshift that generates a unique C-terminal protein sequence absent in healthy cells. This mutant protein is processed by the proteasome into neoantigenic peptides, which are then presented on the cell surface by specific Human Leukocyte Antigen (HLA) class I molecules, most notably HLA-A*02:01 (van der Lee et al., 2019, Cancer Cell). The resulting peptide-HLA complex serves as a highly specific target for the immune system, as it is a true neoantigen with no wild-type counterpart in the human proteome. Therapeutic approaches targeting this complex include T-cell receptor (TCR)-engineered T cells and TCR-mimetic antibodies, which are designed to recognize the specific spatial configuration of the peptide within the HLA groove (Hofmans et al., 2021, Frontiers in Oncology). These immunotherapies aim to provide a potent and selective treatment for AML, potentially reducing the risk of relapse by eliminating minimal residual disease. Clinical development focuses on ensuring high specificity to avoid cross-reactivity with similar self-peptides and addressing mechanisms of resistance such as HLA downregulation.

Other names

NPM1c neoantigenNPM1-mutant peptide-MHC complexHLA-A*02:01-restricted mutant NPM1 peptideMutated nucleophosmin 1 neoepitopeNPM1-mutant pHLA

T-cell mediated cytotoxicity via TCR recognition of the peptide-HLA complex