Correspondence
Nucleophosmin in Acute Myelogenous Leukemia
N Engl J Med 2005; 352:1819-1820April 28, 2005
- Article
To the Editor:
Falini et al. (Jan. 20 issue)1 report an abnormal cytoplasmic localization of nucleophosmin (NPM) in 35 percent of specimens from patients with acute myelogenous leukemia. In these patients the NPM gene was mutated, which resulted in a frame shift. The authors state that tryptophan residues at positions 288 and 290 of NPM played a role in the cytoplasmic translocation of NPM. However, these residues are responsible only for nucleolar localization of NPM, not for cytoplasmic localization.2 We found a motif containing leucine-valine residues, known as the nuclear-export-signal (NES) motif, in the C-terminal of mutated NPMs A to F in Figure 4B of the article (Figure 1Figure 1
Nuclear-Export-Signal (NES) Motif in the C-Terminal of Nucleophosmin (NPM) Mutants.). The typical nuclear-export signal consists of a short stretch of hydrophobic amino acids (predominantly leucines) and fits the consensus sequence Lx(1-3)Lx(2-3)LxL (with x indicating any residues).3 NES-containing molecules are recognized by nuclear export receptor CRM1 and are then exported to cytoplasm.4 We believe that the NES generated by the mutation of the NPM gene is important for cytoplasmic localization of NPM and tumorigenesis in acute myelogenous leukemia.4 ReferencesMasao Nakagawa, M.D.
Yoshihiro Kameoka, M.D.
Ritsuro Suzuki, M.D.
Aichi Cancer Center, Nagoya 464-8681, Japan
mnakagawa@aichi-cc.jp 1
Falini B ,Mecucci C ,Tiacci E , et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005;352:254-266[Erratum, N Engl J Med 2005;352:740.]
Full Text | Web of Science | Medline2
Nishimura Y ,Ohkubo T ,Furuichi Y ,Umekawa H . Tryptophans 286 and 288 in the C-terminal region of protein B23.1 are important for its nucleolar localization. Biosci Biotechnol Biochem 2002;66:2239-2242
CrossRef | Web of Science | Medline3
Henderson BR ,Eleftheriou A . A comparison of the activity, sequence specificity, and CRM1-dependence of different nuclear export signals. Exp Cell Res 2000;256:213-224
CrossRef | Web of Science | Medline4
Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention.
Author/Editor Response
We find the hypothesis of Dr. Nakagawa and colleagues on the mechanism underlying the abnormal cytoplasmic localization of NPM in a subgroup of cases of acute myelogenous leukemias (acute myelogenous leukemia positive for cytoplasmic NPM) very attractive and worth validating experimentally. However, the mechanism of nuclear export might be more complex than they propose, because mutations affecting tryptophans at positions 288 and 290 could also play a role. Tryptophans regulate nucleolar localization of NPM,1 and an inability of the mutated NPM protein to bind to nucleoli may cause its nucleoplasmic accumulation. This defect could facilitate export of the mutated NPM protein, making more of it available for binding to CRM1 through NES. Other NPM mutants will probably be found, and they will indicate whether all NPM mutants bear the same NES motif.
1 ReferencesBrunangelo Falini, M.D.
Cristina Mecucci, M.D., Ph.D.
Massimo F. Martelli, M.D.
Policlinico Monteluce, 06122 Perugia, Italy
faliniem@unipg.it 1
Nishimura Y ,Ohkubo T ,Furuichi Y ,Umekawa H . Tryptophans 286 and 288 in the C-terminal region of protein B23.1 are important for its nucleolar localization. Biosci Biotechnol Biochem 2002;66:2239-2242
CrossRef | Web of Science | Medline
- Citing Articles (17)
Citing Articles
1
Brunangelo Falini, Ilaria Gionfriddo, Federica Cecchetti, Stelvio Ballanti, Valentina Pettirossi, Maria Paola Martelli. (2011) Acute myeloid leukemia with mutated nucleophosmin (NPM1): Any hope for a targeted therapy?. Blood Reviews 25:6, 247-254
CrossRef2
Claudia Sissi, Barbara Gatto, Manlio Palumbo. (2011) The evolving world of protein-G-quadruplex recognition: A medicinal chemist’s perspective. Biochimie 93:8, 1219-1230
CrossRef3
B Falini, N Bolli, A Liso, M P Martelli, R Mannucci, S Pileri, I Nicoletti. (2009) Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia 23:10, 1731-1743
CrossRef4
Firoz Ahmad, Swarna Mandava, Bibhu Ranjan Das. (2009) Mutations of NPM1 gene in de novo acute myeloid leukaemia: determination of incidence, distribution pattern and identification of two novel mutations in Indian population. Hematological Oncology 27:2, 90-97
CrossRef5
N Bolli, M F De Marco, M P Martelli, B Bigerna, A Pucciarini, R Rossi, R Mannucci, N Manes, V Pettirossi, S A Pileri, I Nicoletti, B Falini. (2009) A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF. Leukemia 23:3, 501-509
CrossRef6
Tamotsu Nishida, Yoshiji Yamada. (2008) SMT3IP1, a nucleolar SUMO-specific protease, deconjugates SUMO-2 from nucleolar and cytoplasmic nucleophosmin. Biochemical and Biophysical Research Communications 374:2, 382-387
CrossRef7
Sebastian Scholl, Claudia Theuer, Veit Scheble, Christa Kunert, Anita Heller, Lars-Olof Mügge, Hans-Joerg Fricke, Klaus Höffken, Ulrich Wedding. (2008) Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplications in patients older than 60 yr with acute myeloid leukaemia. European Journal of Haematology 80:3, 208-215
CrossRef8
C G Mullighan, A Kennedy, X Zhou, I Radtke, L A Phillips, S A Shurtleff, J R Downing. (2007) Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. Leukemia 21:9, 2000-2009
CrossRef9
S. Scholl, L.-O. Mügge, O. Landt, I.F. Loncarevic, C. Kunert, J.H. Clement, K. Höffken. (2007) Rapid screening and sensitive detection of NPM1 (nucleophosmin) exon 12 mutations in acute myeloid leukaemia. Leukemia Research 31:9, 1205-1211
CrossRef10
EUN GOO JEONG, SUNG HAK LEE, NAM JIN YOO, SUG HYUNG LEE. (2007) Absence of nucleophosmin 1 (NPM1) gene mutations in common solid cancers. APMIS 115:4, 341-346
CrossRef11
Tomoki Naoe, Tatsuya Suzuki, Hitoshi Kiyoi, Takeshi Urano. (2006) Nucleophosmin: A versatile molecule associated with hematological malignancies. Cancer Science 97:10, 963-969
CrossRef12
A R Mariano, E Colombo, L Luzi, P Martinelli, S Volorio, L Bernard, N Meani, R Bergomas, M Alcalay, P G Pelicci. (2006) Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal. Oncogene 25:31, 4376-4380
CrossRef13
Silvia Grisendi, Cristina Mecucci, Brunangelo Falini, Pier Paolo Pandolfi. (2006) Nucleophosmin and cancer. Nature Reviews Cancer 6:7, 493-505
CrossRef14
P Gorello, G Cazzaniga, F Alberti, M G Dell'Oro, E Gottardi, G Specchia, G Roti, R Rosati, M F Martelli, D Diverio, F Lo Coco, A Biondi, G Saglio, C Mecucci, B Falini. (2006) Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 20:6, 1103-1108
CrossRef15
Viswanathan Palaniswamy, Karen C M Moraes, Carol J Wilusz, Jeffrey Wilusz. (2006) Nucleophosmin is selectively deposited on mRNA during polyadenylation. Nature Structural & Molecular Biology 13:5, 429-435
CrossRef16
Giovanni Roti, Roberto Rosati, Rossella Bonasso, Paolo Gorello, Daniela Diverio, Massimo Fabrizio Martelli, Brunangelo Falini, Cristina Mecucci. (2006) Denaturing High-Performance Liquid Chromatography. The Journal of Molecular Diagnostics 8:2, 254-259
CrossRef17
H Quentmeier, M P Martelli, W G Dirks, N Bolli, A Liso, R A F MacLeod, I Nicoletti, R Mannucci, A Pucciarini, B Bigerna, M F Martelli, C Mecucci, H G Drexler, B Falini. (2005) Cell line OCI/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin. Leukemia 19:10, 1760-1767
CrossRef
