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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1999-2005. Prepublished online as a Blood First Edition Paper on May 23, 2006; DOI 10.1182/blood-2006-03-007013. This Article Full Text (PDF) All Versions of this Article: blood-2006-03-007013v1 108/6/1999    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Falini, B. Articles by Mecucci, C. Search for Related Content PubMed PubMed Citation Articles by Falini, B. Articles by Mecucci, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 2, 2006 Accepted May 8, 2006 Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia Brunangelo Falini*, Maria Paola Martelli, Niccolo Bolli, Rossella Bonasso, Emanuela Ghia, Maria Teresa Pallotta, Daniela Diverio, Ildo Nicoletti, Roberta Pacini, Alessia Tabarrini, Barbara Verducci Galletti, Roberta Mannucci, Giovanni Roti, Roberto Rosati, Giorgina Specchia, Arcangelo Liso, Enrico Tiacci, Myriam Alcalay, Lucilla Luzi, Sara Volorio, Loris Bernard, Anna Guarini, Sergio Amadori, Franco Mandelli, Fabrizio Pane, Francesco Lo Coco, Giuseppe Saglio, Pier-Giuseppe Pelicci, Massimo F Martelli, and Cristina Mecucci Institute of Hematology, University of Perugia, Italy Institute of Hematology, University of Bari, Bari, Italy Institute of Hematology, University 'La Sapienza', Rome, Italy Institute of Internal Medicine, University of Perugia, Italy Institute of Hematology, University of Foggia, Foggia, Italy European Institute of Oncology, Milan, Italy Institute of Hematology University of 'Tor Vergata', Rome, Italy Institute of Hematology Universita 'Federico II', Naples, Italy Division of Internal Medicine and Hematology, Hospital * Corresponding author; email: faliniem{at}unipg.it. Nucleophosmin(NPM) exon-12 mutations occur in 50-60% of adult acute myeloid leukemia (AML) with normal karyotype and are predictors of favourable prognosis. We evaluated bone marrow or peripheral blood samples from 450 adult AMLs of GIMEMA/AML12 EORTC trial to: i) search for new exon-12 NPM mutations; ii) determine whether NPM immunostaining on paraffin-embedded biopsies predicts NPM mutations; and iii) investigate altered nucleo-cytoplasmic NPM traffic in primary AML cells. Fourteen NPM mutations, including 8 new variants, were identified. All 200 AML cases expressing cytoplasmic NPM (NPMc+ AML) carried NPM mutations. None of the 250 cases with nucleus-restricted NPM (NPMc- AML) was mutated. At the C-terminus, NPM leukemic mutants carried mutations of only tryptophan 290 or of both tryptophans 288 and 290 and a new nuclear export signal (NES) motif, which appear to underlie their nuclear export. The specific Crm1/Exportin-1 inhibitor leptomycin-B relocated NPM mutants from cytoplasm to nucleus of primary NPMc+ AML cells, demonstrating that nuclear export is NES-dependent. NPM mutants bound and recruited wild-type NPM into leukemic cell cytoplasm. Because alterations at C-terminus of leukemic NPM mutants are similar, immunohistochemistry detects all exon-12 NPM mutations and is a valuable, inexpensive tool in the diagnostic-prognostic work-up of AML patients with normal karyotype. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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