NPM1-mutated acute myeloid leukemia: from bench to bedside

Abstract
The nucleophosmin (NPM1) gene encodes a versatile protein primarily localized in the nucleolus, where it shuttles between the nucleus and cytoplasm. Mutations in NPM1 are the most common genetic alteration in adult acute myeloid leukemia (AML), occurring in approximately one-third of cases, and they drive the abnormal cytoplasmic mislocalization of mutant NPM1. Due to its distinct characteristics, NPM1-mutated AML is classified as a separate entity in the 2017 World Health Organization (WHO) classification of hematopoietic malignancies.

This review highlights newly discovered functions of wild-type NPM1 in the nucleolus and explores emerging biological and clinical aspects of NPM1-mutated AML. The role of cooperative mutations alongside NPM1 in shaping AML progression and influencing patient outcomes is examined. Additionally, we discuss the necessity of eliminating NPM1-mutated clones to achieve long-term remission and the significance of preleukemic clonal hematopoiesis persistence in increasing the risk of secondary AML.

The involvement of HOX gene expression in the development of NPM1-mutated AML is also emphasized. From a clinical perspective, we address ongoing diagnostic challenges in the 2017 WHO classification of myeloid neoplasms and the crucial role of NPM1 mutations in guiding European LeukemiaNet (ELN) genetic-based risk stratification. Lastly, we assess the strengths and limitations of NPM1-based measurable residual disease (MRD) monitoring in treatment decision-making and highlight promising preclinical findings on XPO1 and menin-MLL inhibitors as potential therapeutic strategies.