Mutant NPM1 in Acute Myeloid Leukemia Initiation and Maintenance

ABSTRACT Background Nucleophosmin (NPM1), a multifunctional nucleolar protein, plays critical roles in ribosome biogenesis, chromatin organization, and genome stability. In one‐third of adult acute myeloid leukemia (AML) cases, mutations in NPM1 , most frequently a 4‐bp insertion in exon 12 generates an aberrant nuclear export signal in C‐terminus, resulting in the cytoplasmic mislocalization of NPM1 (NPM1c). NPM1c defines a distinct molecular entity characterized by aberrant activation of HOXA/B clusters and MEIS1 , which sustain an oncogenic transcriptional program. Aims This review aims to summarize recent advances in the molecular mechanisms of NPM1c‐driven leukemogenesis and discuss its implications for clonal evolution and targeted therapies. Methods and Results Recent findings revealed that NPM1c forms neomorphic chromatin‐bound condensates with the Menin–MLL complex, XPO1, and the super‐elongation complex, amplifying leukemogenic transcriptional hubs while suppressing HDAC activity. Within the framework of age‐associated clonal hematopoiesis (CH), NPM1c acts as a late gatekeeping mutation that transforms preleukemic clones harboring early epigenetic lesions in DNMT3A , TET2 , or IDH1/2 into overt AML cells. Insights from mouse models support this hierarchical evolution and underscore the requirement for cooperating mutations, such as FLT3‐ITD . Emerging therapies including Menin–MLL, XPO1, DOT1L, HBO1, and ENL inhibitors target NPM1c‐driven HOX/MEIS1 dysregulation, whereas early intervention at the CH stage in hematopoietic stem and progenitor cells (HSPCs) harboring IDH or DNMT3A mutations offers a promising preventive strategy. Conclusion This review integrates mechanistic advances from biochemistry, genetic and epigenetic regulation, and clonal evolution to provide a unified model of NPM1c‐mediated leukemogenesis and highlights future directions for precision therapy in AML.