NPM1-mutated acute myeloid leukemia: New pathogenetic and therapeutic insights and open questions

The nucleophosmin (NPM1) gene encodes for a multifunctional chaperone protein that is localized in the nucleolus but continuously shuttles between the nucleus and cytoplasm. NPM1 mutations occur in about one-third of AML, are AML-specific, usually involve exon 12 and are frequently associated with FLT3-ITD, DNMT3A, TET2, and IDH1/2 mutations. Because of its unique molecular and clinico-pathological features, NPM1-mutated AML is regarded as a distinct leukemia entity in both the International Consensus Classification (ICC) and the 5th edition of the World Health Organization (WHO) classification of myeloid neoplasms. All NPM1 mutations generate leukemic mutants that are aberrantly exported in the cytoplasm of the leukemic cells and are relevant to the pathogenesis of the disease. Here, we focus on recently identified functions of the NPM1 mutant at chromatin level and its relevance in driving HOX/MEIS gene expression. We also discuss yet controversial issues of the ICC/WHO classifications, including the biological and clinical significance of therapy-related NPM1-mutated AML and the relevance of blasts percentage in defining NPM1-mutated AML. Finally, we address the impact of new targeted therapies in NPM1-mutated AML with focus on CAR T cells directed against NPM1/HLA neoepitopes, as well as XPO1 and menin inhibitors.