Leukemia linked to gain-of-function mutations of nucleophosmin

09-29-2006

Acute myeloid leukemia (AML) was linked to gain-of-function mutations of nucleophosmin (NPM).

"NPM is a nucleus-cytoplasmic shuttling protein that is implicated in centrosome duplication, cell cycle progression and stress response. At the steady state, NPM localizes mainly in the nucleolus, where it forms a complex with different cellular proteins," investigators in Italy reported.

"One-third of AML are characterized by aberrant cytoplasmic localization of NPM, due to mutations within its last coding exon (exon 12) that cause a frameshift and the formation of novel C-termini," explained A.R. Mariano and colleagues, European Institute of Oncology. "We report here our investigations on the molecular basis for the aberrant localization of mutated NPM. Alignment of the C-terminus of the various NPM mutants revealed the obligatory presence of 4 amino-acid residues that match a CRM1-dependent nuclear export signal (NES).

"Single alanine-substitutions at these sites provoked nuclear re-localization, while fusion of the mutated C-terminus to a heterologous nuclear protein induced CRM1-dependent cytoplasmic localization. Molecular characterization of one exceptional AML carrying cytoplasmic NPM and germ line exon 12 revealed a somatic mutation in the splicing donor site of exon 9 that caused the formation of a functional NES."

The researchers concluded, "It appears, therefore, that AMLs are frequently characterized by gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention."

Mariano and colleagues published their study in Oncogene (Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal. Oncogene, 2006;25(31):4376-4380).

For additional information, contact P.G. Pelicci, European Institute of Oncology, Dept. of Experimental Oncology, Via Ripamonti 435, I-20141 Milan, Italy.

The publisher of the journal Oncogene can be contacted at: Nature Publishing Group, Macmillan Building, 4 Crinan St., London N1 9XW, England.

Keywords: Milan, Italy, AML, Acute Myeloid Leukemia, CRM1, NES, NPM, Nucleus Cytoplasmic Shuttling, Oncology, Nucleophosmin.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.