title: Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: Impact on WHO classification.
abstract: Because of a lack of specific clonality markers, information on lineage involvement and cell of origin of acute myeloid leukemia with normal karyotype (AML-NK), is missing. Because Nucleophosmin (NPM) gene is frequently mutated in AML-NK and causes aberrant NPM cytoplasmic localization (NPMc+), it was used as an AML lineage clonality marker. Clonal NPM exon 12 mutations were detected in myeloid, monocytic, erythroid, and megakaryocytic cells but not in fibroblasts or endothelia that were laser-microdissected from 3 patients with NPMc+ AML. Aberrant cytoplasmic expression of mutated NPM proteins was identified with anti-NPM antibodies in 2 or more myeloid hemopoietic cell lineages in 99 (61.5%) of 161 of NPMc+ AML paraffin-embedded bone marrow biopsies; lymphoid involvement was excluded in 3 investigated cases. These findings suggest that NPMc+ AML derives from either a common myeloid or earlier progenitor. Immunohistochemical studies show that varying combinations and ratios of NPMc+ leukemic cells from distinct lineages are responsible for heterogeneity within each French-American-British (FAB) classification type and for NPMc+ AML falling into different FAB categories. These findings question the value of FAB criteria in subdividing the WHO category of "AML not otherwise characterized" and suggest that, for clinical use, NPMc+ AML be provisionally regarded as a separate AML with prognostic significance.
authors.affiliation: Institute of Hematology, University of Perugia, Perugia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Arcangelo
authors.initials: A
authors.lastname: Liso
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Martelli
authors.forename: Niccolò
authors.initials: N
authors.lastname: Bolli
authors.forename: Roberta
authors.initials: R
authors.lastname: Pacini
authors.forename: Alessia
authors.initials: A
authors.lastname: Tabarrini
authors.forename: Manola
authors.initials: M
authors.lastname: Carini
authors.forename: Barbara
authors.initials: B
authors.lastname: Bigerna
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pucciarini
authors.forename: Roberta
authors.initials: R
authors.lastname: Mannucci
authors.forename: Ildo
authors.initials: I
authors.lastname: Nicoletti
authors.forename: Enrico
authors.initials: E
authors.lastname: Tiacci
authors.forename: Giovanna
authors.initials: G
authors.lastname: Meloni
authors.forename: Giorgina
authors.initials: G
authors.lastname: Specchia
authors.forename: Nicola
authors.initials: N
authors.lastname: Cantore
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.forename: Stefano
authors.initials: S
authors.lastname: Pileri
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
authors.forename: Franco
authors.initials: F
authors.lastname: Mandelli
authors.forename: Massimo Fabrizio
authors.initials: MF
authors.lastname: Martelli
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007621:Karyotyping / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D021381:Protein Transport / Q000235:genetics; D014944:World Health Organization
chemical_list: D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin