Mutant nucleophosmin 1 neoepitope presented by human leukocyte antigen class I (Mutant NPM1-HLA-I)

Mutant nucleophosmin 1 (NPM1) is a frequent genetic alteration in acute myeloid leukemia (AML), occurring in approximately 30% of adult cases (Greiner et al., 2012, Blood). The mutation, typically a 4-base pair insertion in exon 12, causes a frameshift that produces a unique C-terminal protein sequence not found in normal cells. This mutant sequence is processed into neoepitopes and presented on the cell surface by human leukocyte antigen (HLA) class I molecules, such as HLA-A*02:01 (Van der Lee et al., 2019, Blood). These neoepitopes are highly specific to leukemic cells, making them attractive targets for immunotherapy to avoid off-target effects on healthy tissues. Therapeutic strategies include the development of T-cell receptor (TCR) engineered T-cells and bispecific antibodies designed to recognize the specific peptide-HLA complex (Xie et al., 2021, Frontiers in Immunology). Clinical interest is high because NPM1 mutations are often founder mutations, meaning they are present in the majority of leukemic clones and are relatively stable during disease progression.

Other names

NPM1c neoepitopeMutant NPM1-derived HLA-restricted peptideNPM1-mutant peptide-MHC complexNPM1-mutant neoantigenNPM1c-HLA complex

T-cell mediated cytotoxicity triggered by the specific recognition of the mutant NPM1 peptide-HLA class I complex by engineered T-cell receptors or bispecific molecules, leading to the selective lysis of leukemic cells.