Nucleophosmin 1 (NPM1) cytoplasmic mutant (NPM1c)

Nucleophosmin 1 (NPM1) is a multifunctional protein primarily localized in the nucleolus, where it plays critical roles in ribosome biogenesis, centrosome duplication, and the regulation of the p53/ARF tumor suppressor pathway (UniProt P06748). The NPM1c variant is a mutant form resulting from a frame-shift mutation in exon 12, which leads to the loss of the nucleolar localization signal and the acquisition of a nuclear export signal, causing the protein to accumulate in the cytoplasm (Falini et al., 2005, NEJM). This mutation is a defining genetic lesion in approximately 30% of adult acute myeloid leukemia (AML) cases and is recognized as a distinct disease entity by the World Health Organization (Arber et al., 2016, Blood). In the cytoplasm, NPM1c promotes leukemogenesis by disrupting normal hematopoiesis and upregulating a specific set of homeobox (HOX) genes through its interaction with the Menin-KMT2A complex (Issa et al., 2023, Nature). Therapeutic strategies targeting NPM1c include the use of XPO1 inhibitors to prevent its cytoplasmic export and Menin inhibitors to disrupt the downstream transcriptional program (Brunetti et al., 2018, Blood; Krivtsov et al., 2019, Cancer Cell). Because the mutation is specific to the leukemic cells and remains stable throughout the disease course, it is also an invaluable biomarker for monitoring minimal residual disease and predicting clinical outcomes (Ivey et al., 2016, NEJM).

Other names

NPMc+Mutant nucleophosminNPM1-mutatedB23 mutantNucleolar phosphoprotein B23 mutant

Inhibition of the Menin-KMT2A interaction to reverse the HOX/MEIS1 gene expression program, inhibition of XPO1-mediated nuclear export to restore NPM1 to the nucleus, or induction of nucleolar stress and degradation of the mutant protein.