Nucleophosmin 1 W288fs mutant peptide–HLA-A*02:01 complex (NPM1-mut/HLA-A*02:01)

The Nucleophosmin 1 (NPM1) W288fs mutant peptide–HLA-A*02:01 complex is a tumor-specific neoantigen complex found on the surface of leukemic cells in patients with Acute Myeloid Leukemia (AML) (Van der Lee et al., 2019, Blood). The W288fs mutation, also known as the NPM1c mutation, is a frameshift mutation in exon 12 that creates a unique C-terminal sequence not found in the wild-type protein (Greiner et al., 2012, Blood). This mutant protein is processed by the proteasome, and the resulting neo-peptides, such as AIQDLCLAV, are presented by the HLA-A*02:01 molecule (LUMC, 2019). Because this complex is absent from healthy tissues, it represents a highly specific target for immunotherapy, minimizing the risk of on-target/off-tumor toxicity (Van der Lee et al., 2019, Blood). Current therapeutic approaches focus on developing T-cell receptor (TCR)-engineered T cells and TCR-like antibodies designed to recognize the complex with high specificity (Eureka Therapeutics, 2021). Clinical development is particularly relevant for AML patients who harbor the NPM1 mutation, which occurs in approximately 30% of adult cases and is often associated with a favorable prognosis but remains a significant cause of relapse (Falini et al., 2005, NEJM). The complex serves as a critical biomarker for patient selection in clinical trials targeting NPM1-mutant AML.

Other names

NPM1c peptide-HLA-A*02:01 complexNPM1 mutant neoantigenHLA-A*02:01-restricted NPM1mut peptideAIQDLCLAV-HLA-A*02:01 complexNPM1-mutant pMHC complex

Targeted T-cell mediated cytotoxicity via recognition of the specific neoantigen peptide presented on MHC Class I.