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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.
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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.
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