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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 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 Citation Map 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 HighWire 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. Related Collections Oncogenes and Tumor Suppressors Clinical Trials and Observations Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia Brunangelo Falini, Maria Paola Martelli, Niccolò 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, Cristina Mecucci, for the GIMEMA Acute Leukemia Working Party From the Institute of Hematology and the Institute of Internal Medicine, University of Perugia; the Institute of Hematology, University of Bari; the Institute of Hematology, University "La Sapienza," Rome; the Institute of Hematology, University of Foggia; the European Institute of Oncology, Milan; the Institute of Hematology, University of Tor Vergata, Rome; the Institute of Hematology, University "Federico II," Naples; and the Division of Internal Medicine and Hematology, Hospital "S. Luigi," Orbassano, Italy. Nucleophosmin (NPM) exon-12 mutations occur in 50% to 60% of adult acute myeloid leukemia (AML) with normal karyotype and are predictors of favorable prognosis. We evaluated bone marrow or peripheral blood samples from 450 adult patients with AML of the GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto)/AML12 EORTC (European Organization for Research and Treatment of Cancer) trial to (1) search for new exon-12 NPM mutations; (2) determine whether NPM immunostaining on paraffin-embedded biopsies predicts NPM mutations; and (3) investigate altered nucleocytoplasmic 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 patients with AML with normal karyotype. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. S. Laughlin, M. W. Becker, J. L. Liesveld, D. A. Mulford, C. N. Abboud, P. Brown, and P. G. Rothberg Rapid Method for Detection of Mutations in the Nucleophosmin Gene in Acute Myeloid Leukemia J. Mol. Diagn., July 1, 2008; 10(4): 338 - 345. [Abstract] [Full Text] [PDF] F. Lo-Coco, A. Cuneo, F. Pane, D. Cilloni, D. Diverio, M. Mancini, N. Testoni, A. Bardi, B. Izzo, N. Bolli, et al. Prognostic impact of genetic characterization in the GIMEMA LAM99P multicenter study for newly diagnosed acute myeloid leukemia Haematologica, July 1, 2008; 93(7): 1017 - 1024. [Abstract] [Full Text] [PDF] G. Wertheim and A. Bagg Nucleophosmin (NPM1) Mutations in Acute Myeloid Leukemia: An Ongoing (Cytoplasmic) Tale of Dueling Mutations and Duality of Molecular Genetic Testing Methodologies J. Mol. Diagn., May 1, 2008; 10(3): 198 - 202. [Abstract] [Full Text] [PDF] B. Falini, M. P. Martelli, C. Mecucci, A. Liso, N. Bolli, B. Bigerna, A. Pucciarini, S. Pileri, G. Meloni, M. F. Martelli, et al. Cytoplasmic mutated nucleophosmin is stable in primary leukemic cells and in a xenotransplant model of NPMc+ acute myeloid leukemia in SCID mice Haematologica, May 1, 2008; 93(5): 775 - 779. [Abstract] [Full Text] [PDF] R. Garzon, M. Garofalo, M. P. Martelli, R. Briesewitz, L. Wang, C. Fernandez-Cymering, S. Volinia, C.-G. Liu, S. Schnittger, T. Haferlach, et al. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin PNAS, March 11, 2008; 105(10): 3945 - 3950. [Abstract] [Full Text] [PDF] B. Falini, C. Mecucci, G. Saglio, F. L. Coco, D. Diverio, P. Brown, F. Pane, M. Mancini, M. P. Martelli, S. Pileri, et al. NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia Haematologica, March 1, 2008; 93(3): 439 - 442. [Abstract] [Full Text] [PDF] N. Bolli, I. Nicoletti, M. F. De Marco, B. Bigerna, A. Pucciarini, R. Mannucci, M. P. Martelli, A. Liso, C. Mecucci, F. Fabbiano, et al. Born to Be Exported: COOH-Terminal Nuclear Export Signals of Different Strength Ensure Cytoplasmic Accumulation of Nucleophosmin Leukemic Mutants Cancer Res., July 1, 2007; 67(13): 6230 - 6237. [Abstract] [Full Text] [PDF] B. Falini, I. Nicoletti, N. Bolli, M. P. Martelli, A. Liso, P. Gorello, F. Mandelli, C. Mecucci, and M. F. Martelli Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias Haematologica, April 1, 2007; 92(4): 519 - 532. [Abstract] [Full Text] [PDF] B. Falini, I. Nicoletti, M. F. Martelli, and C. Mecucci Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features Blood, February 1, 2007; 109(3): 874 - 885. [Abstract] [Full Text] [PDF] L. Pasqualucci, A. Liso, M. P. Martelli, N. Bolli, R. Pacini, A. Tabarrini, M. Carini, B. Bigerna, A. Pucciarini, R. Mannucci, et al. Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: impact on WHO classification Blood, December 15, 2006; 108(13): 4146 - 4155. [Abstract] [Full Text] [PDF]

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