Background Nucleophosmin (NPM), a nucleocytoplasmic shuttlingprotein with prominent nucleolar localization, regulates theARF-p53 tumor-suppressor pathway. Translocations involving theNPM gene cause cytoplasmic dislocation of the NPM protein.
Methods We used immunohistochemical methods to study the subcellularlocalization of NPM in bone marrow–biopsy specimens from591 patients with primary acute myelogenous leukemia (AML).We then correlated the presence of cytoplasmic NPM with clinicaland biologic features of the disease.
Results Cytoplasmic NPM was detected in 208 (35.2 percent) ofthe 591 specimens from patients with primary AML but not in135 secondary AML specimens or in 980 hematopoietic or extrahematopoieticneoplasms other than AML. It was associated with a wide spectrumof morphologic subtypes of the disease, a normal karyotype,and responsiveness to induction chemotherapy, but not with recurrentgenetic abnormalities. There was a high frequency of FLT3 internaltandem duplications and absence of CD34 and CD133 in AML specimenswith a normal karyotype and cytoplasmic dislocation of NPM,but not in those in which the protein was restricted to thenucleus. AML specimens with cytoplasmic NPM carried mutationsof the NPM gene that were predicted to alter the protein atits C-terminal; this mutant gene caused cytoplasmic localizationof NPM in transfected cells.
Conclusions Cytoplasmic NPM is a characteristic feature of alarge subgroup of patients with AML who have a normal karyotype,NPM gene mutations, and responsiveness to induction chemotherapy.
Source Information
From the Institute of Hematology (B.F., C.M., E.T., R.R., L.P., R.L.S., A.S., B.B., R.P., A.P., M.F.M.) and the Department of Biochemistry and Molecular Biotechnology (V.P.), University of Perugia, Perugia, Italy; the European Institute of Oncology, Milan, Italy (M.A., E.C., N.M., P.-G.P.); the Institute for Cancer Genetics, Columbia University, New York (L.P.); the Institute of Hematology, University La Sapienza, Rome (D.D., F.M.); the Institute of Hematology, University of Foggia, Foggia, Italy (A.L.); the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Rome (M.V., P.F.); the Division of Internal Medicine and Hematology, Ospedale S. Luigi, Orbassano-Turin, Italy (G.S.); and the Department of Biopathology, University of Tor Vergata, Rome (F.L.-C.). Drs. Tiacci, Alcalay, and Rosati contributed equally to this article.
Address reprint requests to Dr. Falini at the Institute of Hematology, Policlinico Monteluce, 06122 Perugia, Italy, or at faliniem{at}unipg.it.
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Verhaak, R. G. W., Goudswaard, C. S., van Putten, W., Bijl, M. A., Sanders, M. A., Hugens, W., Uitterlinden, A. G., Erpelinck, C. A. J., Delwel, R., Lowenberg, B., Valk, P. J. M.
(2005). Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood
106: 3747-3754
[Abstract][Full Text]
Quentmeier, H., Martelli, M. P., Dirks, W. G., Bolli, N., Liso, A., MacLeod, R. A.F., Nicoletti, I., Mannucci, R., Pucciarini, A., Bigerna, B., Martelli, M. F., Mecucci, C., Drexler, H. G., Falini, B.
(2005). Exon-12 Nucleophosmin (NPM) Mutation and Aberrant Cytoplasmic Expression of NPM Protein in Leukemia Cell Line OCI-AML3.. ASH ANNUAL MEETING ABSTRACTS
106: 2376-2376
[Abstract]
Falini, B., Bolli, N., Shan, J., Martelli, M. P., Nicoletti, I., Liso, A., Pasqualucci, L., Rosati, R., Roti, G., Diverio, D., Mannucci, R., Cazzaniga, G., Biondi, A., Saglio, G., Pane, F., Lo-Coco, F., Pelicci, P.-G., Martelli, M. F., Gu, W., Mecucci, C.
(2005). Mechanism of Altered Nucleo-Cytoplasmic Traffic of Nucleophosmin in Acute Myelogenous Leukemia Carrying Exon-12 NPM Mutations (NPMc+ AML).. ASH ANNUAL MEETING ABSTRACTS
106: 4396-4396
[Abstract]
Boissel, N., Renneville, A., Biggio, V., Philippe, N., Thomas, X., Cayuela, J.-M., Terre, C., Tigaud, I., Castaigne, S., Raffoux, E., De Botton, S., Fenaux, P., Dombret, H., Preudhomme, C., for the Acute Leukemia French Association (ALFA),
(2005). Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood
106: 3618-3620
[Abstract][Full Text]
Ammatuna, E., Noguera, N. I., Zangrilli, D., Curzi, P., Panetta, P., Bencivenga, P., Amadori, S., Federici, G., Lo-Coco, F.
(2005). Rapid Detection of Nucleophosmin (NPM1) Mutations in Acute Myeloid Leukemia by Denaturing HPLC. Clin. Chem.
51: 2165-2167
[Full Text]
Colombo, E., Bonetti, P., Lazzerini Denchi, E., Martinelli, P., Zamponi, R., Marine, J.-C., Helin, K., Falini, B., Pelicci, P. G.
(2005). Nucleophosmin Is Required for DNA Integrity and p19Arf Protein Stability. Mol. Cell. Biol.
25: 8874-8886
[Abstract][Full Text]
Suzuki, T., Kiyoi, H., Ozeki, K., Tomita, A., Yamaji, S., Suzuki, R., Kodera, Y., Miyawaki, S., Asou, N., Kuriyama, K., Yagasaki, F., Shimazaki, C., Akiyama, H., Nishimura, M., Motoji, T., Shinagawa, K., Takeshita, A., Ueda, R., Kinoshita, T., Emi, N., Naoe, T.
(2005). Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood
106: 2854-2861
[Abstract][Full Text]
Agnelli, L., Bicciato, S., Mattioli, M., Fabris, S., Intini, D., Verdelli, D., Baldini, L., Morabito, F., Callea, V., Lombardi, L., Neri, A.
(2005). Molecular Classification of Multiple Myeloma: A Distinct Transcriptional Profile Characterizes Patients Expressing CCND1 and Negative for 14q32 Translocations. JCO
23: 7296-7306
[Abstract][Full Text]
Frohling, S., Scholl, C., Gilliland, D. G., Levine, R. L.
(2005). Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications. JCO
23: 6285-6295
[Abstract][Full Text]
Bullinger, L., Valk, P. J.M.
(2005). Gene Expression Profiling in Acute Myeloid Leukemia. JCO
23: 6296-6305
[Abstract][Full Text]
Delaval, B., Letard, S., Lelievre, H., Chevrier, V., Daviet, L., Dubreuil, P., Birnbaum, D.
(2005). Oncogenic Tyrosine Kinase of Malignant Hemopathy Targets the Centrosome. Cancer Res.
65: 7231-7240
[Abstract][Full Text]
Tallman, M. S., Gilliland, D. G., Rowe, J. M.
(2005). Drug therapy for acute myeloid leukemia. Blood
106: 1154-1163
[Abstract][Full Text]
Cazzaniga, G., Dell'Oro, M. G., Mecucci, C., Giarin, E., Masetti, R., Rossi, V., Locatelli, F., Martelli, M. F., Basso, G., Pession, A., Biondi, A., Falini, B.
(2005). Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood
106: 1419-1422
[Abstract][Full Text]
Alcalay, M., Tiacci, E., Bergomas, R., Bigerna, B., Venturini, E., Minardi, S. P., Meani, N., Diverio, D., Bernard, L., Tizzoni, L., Volorio, S., Luzi, L., Colombo, E., Lo Coco, F., Mecucci, C., Falini, B., Pelicci, P. G., for the Gruppo Italiano Malattie Ematologiche Mali,
(2005). Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood
106: 899-902
[Abstract][Full Text]
Nakagawa, M., Kameoka, Y., Suzuki, R., Falini, B., Mecucci, C., Martelli, M. F.
(2005). Nucleophosmin in Acute Myelogenous Leukemia. NEJM
352: 1819-1820
[Full Text]
Ballen, K. K., Hasserjian, R. P.
(2005). Case 2-2005 - A 39-Year-Old Woman with Headache, Stiff Neck, and Photophobia. NEJM
352: 274-283
[Full Text]
Grisendi, S., Pandolfi, P. P.
(2005). NPM Mutations in Acute Myelogenous Leukemia. NEJM
352: 291-292
[Full Text]
Licht, J. D., Sternberg, D. W.
(2005). The Molecular Pathology of Acute Myeloid Leukemia. ASH Education Book
2005: 137-142
[Abstract][Full Text]
A correction has been published: N Engl J Med 2005;352(7):740.
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