LAUSR

Simple Summary The nucleophosmin 1 (NPM1) gene is mutated in approximately one-third of newly diagnosed acute myeloid leukemia (AML) cases. NPM1mutated AML (NPM1mut-AML) has been reclassified as a distinct entity in the 2022 World Health Organization (WHO 2022) and European Leukemia Network (ELN 2022) classification on myeloid neoplasm requiring >10% of leukemic blasts for diagnosis. Clinically, it presents with high white cell counts, blast percentage and frequent extramedullary involvement. In the current era of precision medicine, it carries important diagnostic, clinical and prognostic implications. In this review, we aim to summarize the pathophysiology of the NPM1mut in AML, diagnostic and prognostic challenges and treatment strategies including the use of novel targeted therapeutic agents. Abstract Acute myeloid leukemia (AML) represents 80% of acute leukemia in adults and is characterized by clonal expansion of hematopoietic stem cells secondary to genomic mutations, rendering a selective growth advantage to the mutant clones. NPM1mut is found in around 30% of AML and clinically presents with leukocytosis, high blast percentage and extramedullary involvement. Considered as a “gate-keeper” mutation, NPM1mut appears to be a “first hit” in the process of leukemogenesis and development of overt leukemia. Commonly associated with other mutations (e.g., FLT 3, DNMT3A, TET2, SF3B1), NPM1 mutation in AML has an important role in diagnosis, prognosis, treatment and post-treatment monitoring. Several novel therapies targeting NPM1 are being developed in various clinical phases with demonstration of efficacy. In this review, we summarize the pathophysiology of the NPM1 gene mutation in AML, clinical implications and the novel targeted therapies to date.