Nucleophosmin 1 (NPM1) mutation-derived neoepitope AIQDLCLAV–HLA-A*02:01 complex (NPM1c-HLA-A*02:01)

The Nucleophosmin 1 (NPM1) mutation-derived neoepitope AIQDLCLAV–HLA-A*02:01 complex is a tumor-specific antigen presented on the surface of leukemic cells in patients with Acute Myeloid Leukemia (AML) harboring NPM1 mutations. NPM1 mutations, typically involving a 4-base pair insertion in exon 12, result in a frameshift that generates a novel C-terminal sequence (NPM1c) not found in healthy cells (van der Lee et al., 2019, Cancer Cell). The 9-mer peptide AIQDLCLAV is a highly immunogenic product of this mutation and is specifically presented by the HLA-A*02:01 allele (Hagedoorn et al., 2021, Blood). Because NPM1 mutations are founder mutations present in the majority of leukemic blasts and are essential for the leukemic phenotype, this complex represents an ideal target for immunotherapy. Current therapeutic approaches focus on T-cell receptor (TCR)-engineered T cells and TCR-like antibodies that can recognize this intracellularly derived peptide when presented on the cell surface (Lutteropp et al., 2020, Nature Communications). This target is highly valued for its restricted expression to malignant cells, which minimizes the risk of on-target, off-tumor toxicity in healthy tissues.

Other names

NPM1c neoantigenAIQDLCLAV-HLA-A2 complexMutated Nucleophosmin 1 neoepitopeNPM1-mutant peptide-MHC complex

Targeted recognition of the neoepitope-MHC complex by engineered T-cell receptors or antibodies, leading to T-cell mediated cytotoxicity against leukemic blasts.