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Born to Be Exported: COOH-Terminal Nuclear Export Signals of Different Strength Ensure Cytoplasmic Accumulation of Nucleophosmin Leukemic Mutants

¹ Section of Hematology and Immunology, University of Perugia, IBiT Foundation, Fondazione IRCCS Biotecnologie nel Trapianto; ² Institute of Internal Medicine, University of Perugia, Perugia, Italy; ³ Institute of Hematology, University of Bari, Bari, Italy; ⁴ Institute of Hematology, University of Foggia, Foggia, Italy; ⁵ Institute of Hematology, Ospedale "Cervello," Palermo, Italy; and ⁶ Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, Sydney, Australia

Requests for reprints: Brunangelo Falini, Institute of Hematology, Policlinico, Monteluce, 06122 Perugia, Italy. Phone: 39-075-578-3190; Fax: 39-075-578-3834; E-mail: faliniem{at}unipg.it.

Creation of a nuclear export signal (NES) motif and loss of tryptophans (W) 288 and 290 (or 290 only) at the COOH terminus of nucleophosmin (NPM) are both crucial for NPM aberrant cytoplasmic accumulation in acute myelogenous leukemia (AML) carrying NPM1 mutations. Hereby, we clarify how these COOH-terminal alterations functionally cooperate to delocalize NPM to the cytoplasm. Using a Rev(1.4)-based shuttling assay, we measured the nuclear export efficiency of six different COOH-terminal NES motifs identified in NPM mutants and found significant strength variability, the strongest NES motifs being associated with NPM mutants retaining W288. When artificially coupled with a weak NES, W288-retaining NPM mutants are not exported efficiently into cytoplasm because the force (W288) driving the mutants toward the nucleolus overwhelms the force (NES) exporting the mutants into cytoplasm. We then used this functional assay to study the physiologic NH₂-terminal NES motifs of wild-type NPM and found that they are weak, which explains the prominent nucleolar localization of wild-type NPM. Thus, the opposing balance of forces (tryptophans and NES) seems to determine the subcellular localization of NPM. The fact that W288-retaining mutants always combine with the strongest NES reveals mutational selective pressure toward efficient export into cytoplasm, pointing to this event as critical for leukemogenesis. [Cancer Res 2007;67(13):6230–7]

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