Submitted July 10, 2006
Accepted September 11, 2006
Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biological and clinical features
Brunangelo Falini*, Ildo Nicoletti, Massimo Fabrizio Martelli, and Cristina Mecucci
University of Perugia, Italy
* Corresponding author; email: faliniem{at}unipg.it.
The Nucleophosmin (NPM1) gene encodes for a multifunctional nucleo-cytoplasmic shuttling protein which is mainly localized in the nucleolus. NPM1 mutations occur in 50-60% of adult acute myeloid leukemia with normal karyotype (AML-NK) and generate NPM mutants that localize aberrantly in the leukemic cells cytoplasm; hence the term NPM-cytoplasmic positive (NPMc+ AML). Cytoplasmic NPM accumulation is caused by the concerted action of two alterations at mutant C-terminus, i.e. changes of tryptophan(s) 288 and 290 (or only 290) and creation of an additional nuclear export signal (NES) motif. NPMc+ AML shows increased frequency in adults and female sex, wide morphologic spectrum, multilineage involvement, high frequency of FLT3-ITD, CD34-negativity, and distinct gene expression profile. Analysis of mutated NPM has important clinical and pathological applications. Immunohistochemical detection of cytoplasmic NPM predicts NPM1 mutations and helps rationalize cytogenetic/molecular studies in AML. NPM1 mutations in absence of FLT3-ITD identify a prognostically favourable subgroup in the heterogeneous AML-NK category. Due to their frequency and stability, NPM1 mutations may become a new tool for monitoring minimal residual disease in AML-NK. Future studies should focus on clarifying how NPM mutants promote leukemia, integrating NPMc+ AML in the upcoming World Health Organization leukemia classification, and eventually developing specific anti-leukemic drugs.
