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 wildtype 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1999-2005 |
| Number of pages | 7 |
| Journal | Blood |
| Volume | 108 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Sep 15 2006 |
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ASJC Scopus subject areas
- Hematology
Cite this
Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. / Falini, Brunangelo; Martelli, Maria Paola; Bolli, Niccolò; Bonasso, Rossella; Ghia, Emanuela; Pallotta, Maria Teresa; Diverio, Daniela; Nicoletti, Ildo; Pacini, Roberta; Tabarrini, Alessia; Galletti, Barbara Verducci; Mannucci, Roberta; Roti, Giovanni; Rosati, Roberto; Specchia, Giorgina; Liso, Arcangelo; Tiacci, Enrico; Alcalay, Myriam; Luzi, Lucilla; Volorio, Sara; Bernard, Loris; Guarini, Anna; Amadori, Sergio; Mandelli, Franco; Pane, Fabrizio; Lo-Coco, Francesco; Saglio, Giuseppe; Pelicci, Pier Giuseppe; Martelli, Massimo F.; Mecucci, Cristina.
In: Blood, Vol. 108, No. 6, 15.09.2006, p. 1999-2005.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia
AU - Falini, Brunangelo
AU - Martelli, Maria Paola
AU - Bolli, Niccolò
AU - Bonasso, Rossella
AU - Ghia, Emanuela
AU - Pallotta, Maria Teresa
AU - Diverio, Daniela
AU - Nicoletti, Ildo
AU - Pacini, Roberta
AU - Tabarrini, Alessia
AU - Galletti, Barbara Verducci
AU - Mannucci, Roberta
AU - Roti, Giovanni
AU - Rosati, Roberto
AU - Specchia, Giorgina
AU - Liso, Arcangelo
AU - Tiacci, Enrico
AU - Alcalay, Myriam
AU - Luzi, Lucilla
AU - Volorio, Sara
AU - Bernard, Loris
AU - Guarini, Anna
AU - Amadori, Sergio
AU - Mandelli, Franco
AU - Pane, Fabrizio
AU - Lo-Coco, Francesco
AU - Saglio, Giuseppe
AU - Pelicci, Pier Giuseppe
AU - Martelli, Massimo F.
AU - Mecucci, Cristina
PY - 2006/9/15
Y1 - 2006/9/15
N2 - 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 wildtype 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.
AB - 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 wildtype 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.
UR - http://www.scopus.com/inward/record.url?scp=33748703838&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33748703838&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-03-007013
DO - 10.1182/blood-2006-03-007013
M3 - Article
C2 - 16720834
AN - SCOPUS:33748703838
VL - 108
SP - 1999
EP - 2005
JO - Blood
JF - Blood
SN - 0006-4971
IS - 6
ER -