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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.
 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.
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