• Brunangelo Falini, Cristina Mecucci, Enrico Tiacci, Myriam Alcalay, Roberto Rosati, Laura Pasqualucci, Roberta La Starza, Daniela Diverio, Emanuela Colombo, Antonella Santucci, Barbara Bigerna, Roberta Pacini, Alessandra Pucciarini, Arcangelo Liso, Marco Vignetti, Paola Fazi, Natalia Meani, Valentina Pettirossi, Giuseppe Saglio, Franco Mandelli, Francesco Lo-Coco, Pier-Giuseppe Pelicci, Massimo F Martelli, and GIMEMA Acute Leukemia Working Party.
• Institute of Hematology, University of Perugia, Perugia, Italy. faliniem@unipg.it
• N. Engl. J. Med. 2005 Jan 20; 352 (3): 254-66.

BackgroundNucleophosmin (NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor-suppressor pathway. Translocations involving the NPM gene cause cytoplasmic dislocation of the NPM protein.MethodsWe used immunohistochemical methods to study the subcellular localization of NPM in bone marrow-biopsy specimens from 591 patients with primary acute myelogenous leukemia (AML). We then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease.ResultsCytoplasmic NPM was detected in 208 (35.2 percent) of the 591 specimens from patients with primary AML but not in 135 secondary AML specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of FLT3 internal tandem duplications and absence of CD34 and CD133 in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations of the NPM gene that were predicted to alter the protein at its C-terminal; this mutant gene caused cytoplasmic localization of NPM in transfected cells.ConclusionsCytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy.Copyright 2005 Massachusetts Medical Society.

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