Acute Myeloid Leukemia with Mutated Nucleophosmin

Human nucleophosmin (NPM1), an essential gene, encodes for a ubiquitously expressed protein that plays multiple functions, including stabilization of the Arf tumor suppressor protein, regulation of ribosome biogenesis, and control of centrosome duplication. Although NPM1 constantly shuttles between nucleus and cytoplasm, it resides mainly in the nucleolus. The NPM1 gene is mutated in about one third of adult acute myeloid leukemia (AML) cases. Despite molecular heterogeneity (about 40 variants have been identified to date), all NPM1 mutations determine common alterations at the C-terminus of NPM1 mutant proteins (changes of tryptophans 288 and 290, or 290 alone, and creation of an additional nuclear export signal motif), which cause aberrant NPM1 mutant expression in the cytoplasm of leukemic cells. Acute myeloid leukemia with mutated NPM1 shows distinctive biologic and clinical features, including unique gene expression profile, high frequency of FMS-like tyrosine kinase (FLT3)-internal tandem duplication (ITD), increased incidence in adults and women, wide morphologic spectrum, CD34 negativity, multilineage involvement, and good response to induction therapy. Discovery of mutated NPM1 in AML has already had major diagnostic and clinical implications. Immunohistochemical detection of cytoplasmic nucleophosmin, which is fully predictive of NPM1 mutations, might help rationalize cytogenetic/molecular studies and facilitate genetic classification of AML. Within the heterogeneous category of AML with normal karyotype, NPM1 mutations in the absence of FLT3-ITD identify a subset of patients with favorable prognosis. Because of their stability, NPM1 mutations might become a new tool for monitoring minimal residual disease in about 30% of patients with AML. Understanding how mutations in NPM1 promote leukemia could provide the rationale for the development of targeted therapies.