Nucleophosmin in Acute Myelogenous Leukemia
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《新英格兰医药杂志》
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 1). 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.
Figure 1. Nuclear-Export-Signal (NES) Motif in the C-Terminal of Nucleophosmin (NPM) Mutants.
A short and hydrophobic motif, like a consensus sequence of NES, is found in the C-terminal of all the NPM mutants. Putative residues of an NES are shaded.
Masao Nakagawa, M.D.
Yoshihiro Kameoka, M.D.
Ritsuro Suzuki, M.D.
Aichi Cancer Center
Nagoya 464-8681, Japan
mnakagawa@aichi-cc.jp
References
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.
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.
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.
Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention.
The authors reply: 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.
Brunangelo Falini, M.D.
Cristina Mecucci, M.D., Ph.D.
Massimo F. Martelli, M.D.
Policlinico Monteluce
06122 Perugia, Italy
faliniem@unipg.it
References
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.
Figure 1. Nuclear-Export-Signal (NES) Motif in the C-Terminal of Nucleophosmin (NPM) Mutants.
A short and hydrophobic motif, like a consensus sequence of NES, is found in the C-terminal of all the NPM mutants. Putative residues of an NES are shaded.
Masao Nakagawa, M.D.
Yoshihiro Kameoka, M.D.
Ritsuro Suzuki, M.D.
Aichi Cancer Center
Nagoya 464-8681, Japan
mnakagawa@aichi-cc.jp
References
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.
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.
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.
Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention.
The authors reply: 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.
Brunangelo Falini, M.D.
Cristina Mecucci, M.D., Ph.D.
Massimo F. Martelli, M.D.
Policlinico Monteluce
06122 Perugia, Italy
faliniem@unipg.it
References
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.