Nucleophosmin 1 (NPM1) (NPM1)

Nucleophosmin 1 (NPM1) is a multifunctional nucleolar protein that serves as a critical molecular chaperone, participating in ribosome biogenesis, centrosome duplication, and the regulation of the p53/ARF tumor suppressor pathway. In its physiological state, NPM1 shuttles between the nucleolus and cytoplasm to maintain cellular homeostasis and genomic stability. However, NPM1 is the most frequently mutated gene in adult acute myeloid leukemia (AML), characterized by a frameshift mutation that results in the cytoplasmic mislocalization of the protein (NPM1c+). This mutation creates a unique C-terminal neoantigen that is absent in normal tissues, making NPM1 an ideal source antigen for precision immunotherapy. Therapeutic strategies leveraging NPM1 as a source antigen include TCR-engineered T cells and vaccines designed to recognize mutated peptides, such as the HLA-A*02:01-restricted CLAVEEVSL epitope, presented on the surface of leukemic blasts. Additionally, the oncogenic activity of mutant NPM1 is heavily dependent on the Menin-KMT2A interaction, leading to the clinical development of Menin inhibitors to disrupt the downstream HOX/MEIS1 gene expression program. While targeting the neoantigen offers high specificity, challenges include the potential for differentiation syndrome and the need for patient-specific HLA matching in certain T-cell therapies.

Other names

NucleophosminB23NumatrinNO38Nucleolar phosphoprotein B23Nucleolar protein NO38

T-cell receptor (TCR) recognition of mutated NPM1-derived neoantigens presented on HLA; Inhibition of the Menin-KMT2A complex to disrupt the HOX/MEIS1 oncogenic program; Disruption of NPM1 oligomerization and nucleolar localization; Induction of nucleolar stress.