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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4514-4523. Prepublished online as a Blood First Edition Paper on February 2, 2006; DOI 10.1182/blood-2005-11-4745. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: 2005-11-4745v1 107/11/4514    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Falini, B. Articles by Nicoletti, I. Search for Related Content PubMed PubMed Citation Articles by Falini, B. Articles by Nicoletti, I. Related Collections Related Article in Blood Online Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 30, 2005 Accepted January 21, 2006 Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML Brunangelo Falini*, Niccolo Bolli, Jing Shan, Maria Paola Martelli, Arcangelo Liso, Alessandra Pucciarini, Barbara Bigerna, Laura Pasqualucci, Roberta Mannucci, Roberto Rosati, Paolo Gorello, Daniela Diverio, Giovanni Roti, Enrico Tiacci, Giovanni Cazzaniga, Andrea Biondi, Suzanne Schnittger, Torsten Haferlach, Wolfgang Hiddemann, Massimo F Martelli, Wei Gu, Cristina Mecucci, and Ildo Nicoletti Institute of Hematology and Internal Medicine, University of Perugia, Perugia, Italy Institute for Cancer Genetics and Department of Pathology, Columbia University, New York, NY, USA Institute of Hematology, University of Bari, Bari, Italy Institute of Hematology, University of Foggia, Foggia, Italy Institute of Hematology, University La Sapienza, Roma, Italy Pediatric Clinic, M. Tettamanti Research Center, San Gerardo Hospital, Monza, Italy Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilian University, Munich, Germany * Corresponding author; email: faliniem{at}unipg.it. We recently identified aberrant cytoplasmic expression of nucleophosmin (NPM) as the immunohistochemical marker of a large subgroup of acute myeloid leukemia (AML) (about one-third of adult AML) which are characterized by normal karyotype and mutations occurring at the exon-12 of NPM gene. In this paper, we have elucidated the molecular mechanism underlying the abnormal cytoplasmic localization of NPM. All 30 AML-associated mutated NPM alleles so far identified encode abnormal proteins which have acquired at the C-terminus a nuclear export signal-(NES) motif and lost both tryptophan residues 288 and 290 (or only the residue 290) which determine nucleolar localization. We show for the first time that both alterations are crucial for NPM mutant export from nucleus to cytoplasm. In fact, the cytoplasmic accumulation of NPM is blocked by leptomycin-B and ratjadones, specific exportin-1/Crm1-inhibitors, and by re-insertion of tryptophan residues 288 and 290, which respectively relocate NPM mutants in the nucleoplasm and nucleoli. NPM leukemic mutants in turn recruit the wild-type NPM from nucleoli to nucleoplasm and cytoplasm. These findings indicate that potential therapeutic strategies aimed to re-target NPM to its physiological sites will have to overcome two obstacles, the new NES motif and the mutated tryptophan(s) at the NPM mutants C-terminus. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Rush hour in AML: news on NPM traffic Konstanze Döhner and Hartmut Döhner Blood 2006 107: 4200-4201. [Full Text] [PDF] Related Letter in Blood Online: High frequency of NPM1 gene mutations in acute myeloid leukemia with prominent nuclear invaginations ("cuplike" nuclei) Weina Chen, Georgios Z. Rassidakis, Jiang Li, Mark Routbort, Daniel Jones, Hagop Kantarjian, L. Jeffrey Medeiros, and Carlos E. Bueso-Ramos Blood 2006 108: 1783-1784. [Full Text] [PDF] This article has been cited by other articles: K. L. Inder, C. Lau, D. Loo, N. Chaudhary, A. Goodall, S. Martin, A. Jones, D. van der Hoeven, R. G. Parton, M. M. Hill, et al. Nucleophosmin and Nucleolin Regulate K-Ras Plasma Membrane Interactions and MAPK Signal Transduction J. Biol. Chem., October 9, 2009; 284(41): 28410 - 28419. [Abstract] [Full Text] [PDF] J. G. Turner, D. C. Marchion, J. L. Dawson, M. F. Emmons, L. A. Hazlehurst, P. Washausen, and D. M. Sullivan Human Multiple Myeloma Cells Are Sensitized to Topoisomerase II Inhibitors by CRM1 Inhibition Cancer Res., September 1, 2009; 69(17): 6899 - 6905. [Abstract] [Full Text] [PDF] F. Scaloni, S. Gianni, L. Federici, B. Falini, and M. Brunori Folding mechanism of the C-terminal domain of nucleophosmin: residual structure in the denatured state and its pathophysiological significance FASEB J, August 1, 2009; 23(8): 2360 - 2365. [Abstract] [Full Text] [PDF] C. G. Grummitt, F. M. Townsley, C. M. Johnson, A. J. Warren, and M. Bycroft Structural Consequences of Nucleophosmin Mutations in Acute Myeloid Leukemia J. Biol. Chem., August 22, 2008; 283(34): 23326 - 23332. [Abstract] [Full Text] [PDF] A. Liso, F. Castiglione, A. Cappuccio, F. Stracci, R. F. Schlenk, S. Amadori, C. Thiede, S. Schnittger, P. J.M. Valk, K. Dohner, et al. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1) Haematologica, August 1, 2008; 93(8): 1219 - 1226. [Abstract] [Full Text] [PDF] T. S. Laughlin, M. W. Becker, J. L. Liesveld, D. A. Mulford, C. N. Abboud, P. Brown, and P. G. Rothberg Rapid Method for Detection of Mutations in the Nucleophosmin Gene in Acute Myeloid Leukemia J. Mol. Diagn., July 1, 2008; 10(4): 338 - 345. [Abstract] [Full Text] [PDF] B. Falini, M. P. Martelli, C. Mecucci, A. Liso, N. Bolli, B. Bigerna, A. Pucciarini, S. Pileri, G. Meloni, M. F. Martelli, et al. Cytoplasmic mutated nucleophosmin is stable in primary leukemic cells and in a xenotransplant model of NPMc+ acute myeloid leukemia in SCID mice Haematologica, May 1, 2008; 93(5): 775 - 779. [Abstract] [Full Text] [PDF] R. Garzon, M. Garofalo, M. P. Martelli, R. Briesewitz, L. Wang, C. Fernandez-Cymering, S. Volinia, C.-G. Liu, S. Schnittger, T. Haferlach, et al. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin PNAS, March 11, 2008; 105(10): 3945 - 3950. [Abstract] [Full Text] [PDF] B. Falini, C. Mecucci, G. Saglio, F. L. Coco, D. Diverio, P. Brown, F. Pane, M. Mancini, M. P. Martelli, S. Pileri, et al. NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia Haematologica, March 1, 2008; 93(3): 439 - 442. [Abstract] [Full Text] [PDF] N. Bolli, I. Nicoletti, M. F. De Marco, B. Bigerna, A. Pucciarini, R. Mannucci, M. P. Martelli, A. Liso, C. Mecucci, F. Fabbiano, et al. Born to Be Exported: COOH-Terminal Nuclear Export Signals of Different Strength Ensure Cytoplasmic Accumulation of Nucleophosmin Leukemic Mutants Cancer Res., July 1, 2007; 67(13): 6230 - 6237. [Abstract] [Full Text] [PDF] B. Falini, I. Nicoletti, N. Bolli, M. P. Martelli, A. Liso, P. Gorello, F. Mandelli, C. Mecucci, and M. F. Martelli Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias Haematologica, April 1, 2007; 92(4): 519 - 532. [Abstract] [Full Text] [PDF] B. Falini, I. Nicoletti, M. F. Martelli, and C. Mecucci Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features Blood, February 1, 2007; 109(3): 874 - 885. [Abstract] [Full Text] [PDF] T. Lechertier, V. Sirri, D. Hernandez-Verdun, and P. Roussel A B23-interacting sequence as a tool to visualize protein interactions in a cellular context J. Cell Sci., January 15, 2007; 120(2): 265 - 275. [Abstract] [Full Text] [PDF] K. Mrozek, G. Marcucci, P. Paschka, S. P. Whitman, and C. D. Bloomfield Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood, January 15, 2007; 109(2): 431 - 448. [Abstract] [Full Text] [PDF] D. Grimwade NPM1 mutation in AML: WHO and why? Blood, December 15, 2006; 108(13): 3965 - 3965. [Full Text] [PDF] L. Pasqualucci, A. Liso, M. P. Martelli, N. Bolli, R. Pacini, A. Tabarrini, M. Carini, B. Bigerna, A. Pucciarini, R. Mannucci, et al. Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: impact on WHO classification Blood, December 15, 2006; 108(13): 4146 - 4155. [Abstract] [Full Text] [PDF] N. Bolli, M. Paola Martelli, B. Bigerna, A. Pucciarini, B. Verducci, T. Pallotta, F. de Marco, V. Pettirossi, R. Mannucci, E. Bonifacio, et al. Reciprocal Interaction between NPM Leukemic Mutants and Arf: Structural Basis and Functional Consequences. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 1939 - 1939. [Abstract] [PDF] B. Falini, M. P. Martelli, N. Bolli, R. Bonasso, E. Ghia, M. T. Pallotta, D. Diverio, I. Nicoletti, R. Pacini, A. Tabarrini, et al. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia Blood, September 15, 2006; 108(6): 1999 - 2005. [Abstract] [Full Text] [PDF] W. Chen, G. Z. Rassidakis, J. Li, M. Routbort, D. Jones, H. Kantarjian, L. J. Medeiros, and C. E. Bueso-Ramos High frequency of NPM1 gene mutations in acute myeloid leukemia with prominent nuclear invaginations ("cuplike" nuclei). Blood, September 1, 2006; 108(5): 1783 - 1784. [Full Text] [PDF] T. Enomoto, M. S. Lindstrom, A. Jin, H. Ke, and Y. Zhang Essential Role of the B23/NPM Core Domain in Regulating ARF Binding and B23 Stability J. Biol. Chem., July 7, 2006; 281(27): 18463 - 18472. [Abstract] [Full Text] [PDF]

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