Pathogenesis of Acute Myeloid Leukemia: A Literature Review with A Focus on NPM1 Mutations and Their Molecular Implications

Abstract

Background: Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy characterized by the accumulation of abnormal myeloid precursor cells in the bone marrow and peripheral blood, interfering with normal hematopoiesis. AML is the most common acute leukemia in adults and presents with a heterogeneous clinical course, making timely diagnosis and treatment critical for improving outcomes. NPM1 mutations are among the most frequent genetic abnormalities in AML, especially in patients with normal karyotypes, and play a key role in disease classification, prognosis, and the development of targeted treatments. Objective: This review provides a comprehensive overview on the classification, diagnosis and management of AML, with a particular focus on the structural and functional consequences of NPM1 mutations, their co-occurrence with other recurrent genetic abnormalities and discusses their impact on diagnosis, risk stratification, prognosis, and emerging therapeutic strategies. Methods: An extensive literature review was conducted, synthesizing findings from recent preclinical and clinical studies, updated classification frameworks, and molecular profiling analyses to elucidate the role of NPM1 mutations in AML pathogenesis and clinical management. Results: NPM1-mutated (NPM1c) AML exhibits distinct genetic, epigenetic, and transcriptomic features, including Homeobox (HOX) gene overexpression, impaired TP53-mediated apoptosis, and frequent co-mutations in genes such as Fms-like tyrosine kinase 3 (FLT3), DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A), and Isocitrate dehydrogenase (IDH). Although NPM1 mutations are generally linked to favorable outcomes, this prognosis can worsen in the presence of high-risk co-mutations. Advances in molecular diagnostics and measurable residual disease (MRD) monitoring have enhanced risk stratification, while emerging targeted therapies such as retinoic acid, BCL-2 and menin inhibitors, and immune-based strategies are promising in preclinical and early clinical trials. Conclusion: NPM1 mutations define a biologically and clinically distinct AML subtype with evolving diagnostic and therapeutic interventions. Future research should prioritize the optimization of personalized treatment through neoantigen-based immunotherapies, single-cell transcriptomics, CRISPR-engineered models, and combinatorial strategies that target epigenetic and immune evasion pathways.