Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features.

Abstract

The nucleophosmin (NPM1) gene encodes for a multifunctional nucleocytoplasmic shuttling protein that is localized mainly in the nucleolus. NPM1 mutations occur in 50% to 60% of adult acute myeloid leukemia with normal karyotype (AML-NK) and generate NPM mutants that localize aberrantly in the leukemic-cell cytoplasm, hence the term NPM-cytoplasmic positive (NPMc+ AML). Cytoplasmic NPM accumulation is caused by the concerted action of 2 alterations at mutant C-terminus, that is, 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 females, wide morphologic spectrum, multilineage involvement, high frequency of FLT3-ITD, CD34 negativity, and a distinct gene-expression profile. Analysis of mutated NPM has important clinical and pathologic 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 favorable 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 antileukemic drugs.

• Authors: Brunangelo Falini, Ildo Nicoletti, Massimo F Martelli, Cristina Mecucci
• Journal: Blood (Blood) Vol. 109 Issue 3 Pg. 874-85 (Feb 01 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17008539 (Publication Type: Journal Article, Review)

Chemical References

• NPM1 protein, human
• Nuclear Proteins
• Nucleophosmin

Topics

• Active Transport, Cell Nucleus
• Acute Disease
• Cytoplasm (chemistry)
• Humans
• Leukemia, Myeloid (diagnosis, etiology, genetics)
• Mutation
• Nuclear Proteins (genetics)
• Nucleophosmin