title: Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia.
abstract: 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.
authors.affiliation: Institute of Hematology, Policlinico Monteluce, 06122 Perugia, Italy. faliniem@unipg.it
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Martelli
authors.forename: Niccolò
authors.initials: N
authors.lastname: Bolli
authors.forename: Rossella
authors.initials: R
authors.lastname: Bonasso
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ghia
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pallotta
authors.forename: Daniela
authors.initials: D
authors.lastname: Diverio
authors.forename: Ildo
authors.initials: I
authors.lastname: Nicoletti
authors.forename: Roberta
authors.initials: R
authors.lastname: Pacini
authors.forename: Alessia
authors.initials: A
authors.lastname: Tabarrini
authors.forename: Barbara Verducci
authors.initials: BV
authors.lastname: Galletti
authors.forename: Roberta
authors.initials: R
authors.lastname: Mannucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Roti
authors.forename: Roberto
authors.initials: R
authors.lastname: Rosati
authors.forename: Giorgina
authors.initials: G
authors.lastname: Specchia
authors.forename: Arcangelo
authors.initials: A
authors.lastname: Liso
authors.forename: Enrico
authors.initials: E
authors.lastname: Tiacci
authors.forename: Myriam
authors.initials: M
authors.lastname: Alcalay
authors.forename: Lucilla
authors.initials: L
authors.lastname: Luzi
authors.forename: Sara
authors.initials: S
authors.lastname: Volorio
authors.forename: Loris
authors.initials: L
authors.lastname: Bernard
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Franco
authors.initials: F
authors.lastname: Mandelli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Pier-Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Martelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
mesh_terms: D021581:Active Transport, Cell Nucleus; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D003593:Cytoplasm / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D049790:Nuclear Export Signals / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000090243:Nucleophosmin; D014364:Tryptophan / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; C000716967:NPM1 protein, human; D049790:Nuclear Export Signals; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D014364:Tryptophan