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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4146-4155.
Prepublished online as a Blood First Edition Paper on August 22, 2006; DOI 10.1182/blood-2006-06-026716.
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Submitted June 5, 2006
Accepted August 1, 2006
Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: Impact on WHO classification
Laura Pasqualucci, Arcangelo Liso, Maria Paola Martelli, Niccolo Bolli, Roberta Pacini, Alessia Tabarrini, Manola Carini, Barbara Bigerna, Alessandra Pucciarini, Roberta Mannucci, Ildo Nicoletti, Enrico Tiacci, Giovanna Meloni, Giorgina Specchia, Nicola Cantore, Francesco Di Raimondo, Stefano Pileri, Cristina Mecucci, Franco Mandelli, Massimo Fabrizio Martelli, and Brunangelo Falini*
Institute for Cancer Genetics, Columbia University, New York, NY, USA
Institute of Hematology, University of Foggia, Foggia, Italy
Institute of Hematology, University of Bari, Bari, Italy
Institute of Hematology, University of Perugia, Perugia, Italy
Institute of Internal Medicine, University of Perugia, Perugia, Italy
Institute of Hematology, University "La Sapienza", Rome, Italy
Hematogy Service, "Moscati" Hospital, Avellino, Italy
Institute of Hematology, Institute of Hematology; "Ferrarotto" Hospital, Catania, Italy
Institute of Hematology, Policlinico S. Orsola, Bologna, Italy
* Corresponding author; email: faliniem{at}unipg.it.
Due to lack of specific clonality markers, information on lineage involvement and cell of origin of most acute myeloid leukemias (AMLs), especially those with normal karyotype (AML-NK), is missing. As Nucleophosmin (NPM) exon-12 gene is frequently mutated in AML-NK and causes aberrant NPM cytoplasmic localization (NPMc+), it was used as 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 NPMc+ AML. Aberrant cytoplasmic expression of mutated NPM proteins was identified with anti-NPM antibodies in two or more myeloid hemopoietic cell lineages in 99/161 (61.5%) of NPMc+ AML paraffin-embedded bone marrow biopsies; lymphoid involvement was excluded in three 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 leukemic cells from distinct lineages are responsible for heterogeneity within each FAB 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.
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