HLA class I-presented mutant nucleophosmin 1 peptide (HLA-NPM1mut)

The HLA class I-presented mutant nucleophosmin 1 (NPM1) peptide is a highly specific neoantigen found on the surface of leukemic cells in approximately 30% of adult acute myeloid leukemia (AML) cases (Falini et al., 2005, NEJM). Mutations in the NPM1 gene, typically a 4-base pair insertion in exon 12, result in a frameshift that generates a novel C-terminal protein sequence that is entirely absent in healthy tissues. This mutant protein is processed by the proteasome, and the resulting neo-peptides are presented by Human Leukocyte Antigen (HLA) class I molecules, most notably HLA-A*02:01 (van der Lee et al., 2019, Cancer Cell). Because of its high tumor specificity and lack of expression in normal cells, this complex serves as an ideal target for immunotherapy, particularly T-cell receptor (TCR)-engineered T cells and TCR-like bispecific antibodies (Xie et al., 2021, Nature Communications). Targeting this neoantigen offers a precision medicine approach for NPM1-mutated AML, which is a distinct clinical entity with specific prognostic implications. Current research focuses on identifying high-affinity TCRs that can effectively recognize the peptide-MHC complex without cross-reacting with the wild-type NPM1 protein found in healthy cells.

Other names

NPM1-mutant neoantigenNPM1c-derived HLA-presented peptideNPM1-mutant pMHC complexNucleophosmin 1 mutant neoepitopeHLA-A*02:01-restricted mutant NPM1 peptide

Recognition of the mutant peptide-HLA complex by engineered T-cell receptors (TCRs) or TCR-like molecules, which triggers T-cell activation, secretion of cytotoxic granules (perforin/granzyme), and targeted lysis of NPM1-mutated leukemic cells (van der Lee et al., 2019, Cancer Cell).