NPM Mutations in Acute Myelogenous Leukemia
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《新英格兰医药杂志》
Nucleophosmin (NPM) is a multifunctional phosphoprotein to which both tumor-suppressor and oncogenic functions have been attributed. Chromosomal translocations involving the NPM1 gene occur not infrequently in myeloid and lymphoid cancers. The NPM1 gene rearranges with the retinoic acid receptor (RAR) gene in acute promyelocytic leukemia and with the anaplastic lymphoma kinase (ALK) gene in a high percentage of anaplastic large-cell lymphomas. Rearrangements with the myeloid leukemia factor 1 (MLF1) gene occur in acute myelogenous leukemia (AML), chronic myelogenous leukemia, and myelodysplasia.1,2,3 As a consequence of these translocations, the rearranged NPM1 allele encodes a fusion protein, and the cancer cells become hemizygous for the NPM1 gene, thereby delivering a two-pronged genetic insult to the cells. The fusion proteins might perturb the activity of the already low levels of NPM protein, because of their ability to form dimers with the wild-type protein. The relevance of down-regulation of NPM with respect to oncogenesis is bolstered by the finding that in several cancers, deletion of the long arm of chromosome 5, where NPM resides, is often observed. However, NPM is also frequently overexpressed in both solid tumors and lymphoid cancers.
In this issue of the Journal, Falini and colleagues4 report that NPM1 is mutated in a high proportion of cases of AML and that such cases have distinctive biologic and clinical features. These findings underscore the importance of deregulated NPM in tumorigenesis and have diagnostic and clinical relevance. AML is a highly heterogeneous group of disorders. Molecular genetics has significantly facilitated the classification of these diseases and the development of targeted therapies. For example, types of AML associated with specific chromosomal translocations — for example, the t(15;17) translocation of acute promyelocytic leukemia — respond to targeted therapies and identify distinct prognostic subgroups. Nevertheless, up to 50 percent of cases have no diagnostic chromosomal abnormalities. Furthermore, high-throughput genetic analysis (e.g., microarray analysis), though useful in identifying distinct treatment-response groups, has not yet revealed subgroups of AML that transcend those already recognized on the basis of recurrent chromosomal translocations.
Falini and colleagues report that mutations in NPM1 cause an aberrant cytoplasmic localization of the protein (NPMc+), which can easily be detected by immunohistochemistry. These NPMc+ leukemias, which constitute about one third of cases of primary AML in adults, have distinctive features. Most of them retain normal karyotypes and harbor mutations in the Fms-like tyrosine kinase (FLT3) gene. Moreover, there is a wide morphologic spectrum and multilineage involvement among these cases. The leukemic cells do not, however, express the multilineage stem-cell marker CD34, suggesting that the cell of origin might be a relatively differentiated hematopoietic progenitor cell. Lastly, NPMc+ AML responds well to induction therapy. This observation and the normal karyotype place NPMc+ AML in an intermediate-risk category. Further studies are needed to determine whether NPMc+ predicts a favorable long-term outcome.
Although a causal relation between NPMc+ status and leukemogenesis needs to be established, the identification of NPMc+ AML raises intriguing mechanistic questions because NPM is a protein with diverse functions that occur in distinct subcellular compartments. Four main functions have been attributed to NPM (Figure 1): promotion of the biogenesis of the ribosome by acting as a chaperone that carries preribosomal particles from the nucleolus (where NPM normally accumulates) to the cytoplasm and by favoring the processing and maturation of ribosomal RNA5; control of the duplication of the centrosome during the cell cycle6; modulation of the function of tumor-suppressor transcription factors, such as interferon regulatory factor 1 (IRF-1) and p53 in the nucleoplasm7,8; and regulation of the function and stability of the p19ARF tumor suppressor.9 That NPM controls the p19ARF–p53 tumor suppressor pathway at multiple levels may suggest a tumor-suppressor role for NPM itself. However, NPM, when overproduced, can transform immortalized cells and is highly expressed in tumors of various histologic origins and in actively proliferating cells, in agreement with its role in ribosome biogenesis.
Figure 1. Nuclear and Cytoplasmic Nucleophosmin.
Nucleophosmin (NPM) is a nucleolar phosphoprotein that shuttles between the nuclear and cytoplasmic compartments of the cell. NPM has several interacting partners and diverse functions, among which are the biogenesis of ribosomes and the control of centrosome duplication. Nucleophosmin physically and functionally interacts with p53 and p19ARF, proteins that have crucial roles in tumor suppression. In the study by Falini et al.,4 a cytoplasmic, mutated version of NPM (termed NPMc+) was found in about one third of cases of acute myelogenous leukemia (AML) of all morphologic types and of all French–American–British classification subtypes except M3, M4eo, and M7. NPMc+ lacked the nucleolar localization signal and accumulated in the cytoplasm of leukemia cells. NPMc+ may cause displacement of wild-type NPM through dimerization. The outcomes of NPM retention in the cytoplasm are unknown but are probably complex. The presence of NPMc+ in leukemic blasts was associated with a normal karyotype and a relatively good response to induction chemotherapy. The NPMc+ subtype of AML was CD34-negative and CD133-negative and was associated with the presence of tandem duplications of the FLT3 gene.
Mutations of NPM in AML disrupt the NPM nucleolar-localization signal, causing accumulation of NPM in the cytoplasm. Although the mutation occurs in only one allele of the gene, NPM staining in NPMc+ AML is mostly cytoplasmic. This finding suggests that the mutant NPM acts dominantly on the product of the remaining wild-type allele, causing its retention in the cytoplasm by heterodimerization.
The complex, multifunctional role of NPM makes it difficult to predict the possible outcomes of its delocalization from the nucleus. Loss of nuclear NPM function might impair the p53 pathway. However, functional loss of NPM function might also impair ribosome biogenesis and thus oppose oncogenic transformation. Moreover, a severe loss in the function of p53 would be at odds with the normal karyotype of NPMc+ AML, because a lack of p53 causes genetic instability. Conversely, NPMc+ might also act as a gain-of-function mutant that triggers oncogenesis from the cytosol by unidentified mechanisms. The only known function of NPM in the cytosol that does not depend on its ability to shuttle to and from the nucleus concerns the control of centrosome duplication. Anomalies in the centrosome cycle often cause aneuploidy, which is common in cancer. The finding that NPMc+ AML is associated with a normal karyotype may suggest that the mutated NPMc+ protein still functions normally at the centrosome.
Whatever its role in leukemogenesis may turn out to be, the identification of cytoplasmic NPM in a high proportion of cases of AML is an important finding, not only because it has clinical implications but also because it calls for further studies of the molecular basis of the role of NPM in oncogenesis.
Source Information
From the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York.
References
Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994;263:1281-1284.
Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996;87:882-886.
Yoneda-Kato N, Look AT, Kirstein MN, et al. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 1996;12:265-275.
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.
Ruggero D, Pandolfi PP. Does the ribosome translate cancer? Nat Rev Cancer 2003;3:179-192.
Okuda M, Horn HF, Tarapore P, et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 2000;103:127-140.
Kondo T, Minamino N, Nagamura-Inoue T, Matsumoto M, Taniguchi T. Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity. Oncogene 1997;15:1275-1281.
Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG. Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol 2002;4:529-533.
Bertwistle D, Sugimoto M, Sherr CJ. Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Mol Cell Biol 2004;24:985-996.(Silvia Grisendi, Ph.D., a)
In this issue of the Journal, Falini and colleagues4 report that NPM1 is mutated in a high proportion of cases of AML and that such cases have distinctive biologic and clinical features. These findings underscore the importance of deregulated NPM in tumorigenesis and have diagnostic and clinical relevance. AML is a highly heterogeneous group of disorders. Molecular genetics has significantly facilitated the classification of these diseases and the development of targeted therapies. For example, types of AML associated with specific chromosomal translocations — for example, the t(15;17) translocation of acute promyelocytic leukemia — respond to targeted therapies and identify distinct prognostic subgroups. Nevertheless, up to 50 percent of cases have no diagnostic chromosomal abnormalities. Furthermore, high-throughput genetic analysis (e.g., microarray analysis), though useful in identifying distinct treatment-response groups, has not yet revealed subgroups of AML that transcend those already recognized on the basis of recurrent chromosomal translocations.
Falini and colleagues report that mutations in NPM1 cause an aberrant cytoplasmic localization of the protein (NPMc+), which can easily be detected by immunohistochemistry. These NPMc+ leukemias, which constitute about one third of cases of primary AML in adults, have distinctive features. Most of them retain normal karyotypes and harbor mutations in the Fms-like tyrosine kinase (FLT3) gene. Moreover, there is a wide morphologic spectrum and multilineage involvement among these cases. The leukemic cells do not, however, express the multilineage stem-cell marker CD34, suggesting that the cell of origin might be a relatively differentiated hematopoietic progenitor cell. Lastly, NPMc+ AML responds well to induction therapy. This observation and the normal karyotype place NPMc+ AML in an intermediate-risk category. Further studies are needed to determine whether NPMc+ predicts a favorable long-term outcome.
Although a causal relation between NPMc+ status and leukemogenesis needs to be established, the identification of NPMc+ AML raises intriguing mechanistic questions because NPM is a protein with diverse functions that occur in distinct subcellular compartments. Four main functions have been attributed to NPM (Figure 1): promotion of the biogenesis of the ribosome by acting as a chaperone that carries preribosomal particles from the nucleolus (where NPM normally accumulates) to the cytoplasm and by favoring the processing and maturation of ribosomal RNA5; control of the duplication of the centrosome during the cell cycle6; modulation of the function of tumor-suppressor transcription factors, such as interferon regulatory factor 1 (IRF-1) and p53 in the nucleoplasm7,8; and regulation of the function and stability of the p19ARF tumor suppressor.9 That NPM controls the p19ARF–p53 tumor suppressor pathway at multiple levels may suggest a tumor-suppressor role for NPM itself. However, NPM, when overproduced, can transform immortalized cells and is highly expressed in tumors of various histologic origins and in actively proliferating cells, in agreement with its role in ribosome biogenesis.
Figure 1. Nuclear and Cytoplasmic Nucleophosmin.
Nucleophosmin (NPM) is a nucleolar phosphoprotein that shuttles between the nuclear and cytoplasmic compartments of the cell. NPM has several interacting partners and diverse functions, among which are the biogenesis of ribosomes and the control of centrosome duplication. Nucleophosmin physically and functionally interacts with p53 and p19ARF, proteins that have crucial roles in tumor suppression. In the study by Falini et al.,4 a cytoplasmic, mutated version of NPM (termed NPMc+) was found in about one third of cases of acute myelogenous leukemia (AML) of all morphologic types and of all French–American–British classification subtypes except M3, M4eo, and M7. NPMc+ lacked the nucleolar localization signal and accumulated in the cytoplasm of leukemia cells. NPMc+ may cause displacement of wild-type NPM through dimerization. The outcomes of NPM retention in the cytoplasm are unknown but are probably complex. The presence of NPMc+ in leukemic blasts was associated with a normal karyotype and a relatively good response to induction chemotherapy. The NPMc+ subtype of AML was CD34-negative and CD133-negative and was associated with the presence of tandem duplications of the FLT3 gene.
Mutations of NPM in AML disrupt the NPM nucleolar-localization signal, causing accumulation of NPM in the cytoplasm. Although the mutation occurs in only one allele of the gene, NPM staining in NPMc+ AML is mostly cytoplasmic. This finding suggests that the mutant NPM acts dominantly on the product of the remaining wild-type allele, causing its retention in the cytoplasm by heterodimerization.
The complex, multifunctional role of NPM makes it difficult to predict the possible outcomes of its delocalization from the nucleus. Loss of nuclear NPM function might impair the p53 pathway. However, functional loss of NPM function might also impair ribosome biogenesis and thus oppose oncogenic transformation. Moreover, a severe loss in the function of p53 would be at odds with the normal karyotype of NPMc+ AML, because a lack of p53 causes genetic instability. Conversely, NPMc+ might also act as a gain-of-function mutant that triggers oncogenesis from the cytosol by unidentified mechanisms. The only known function of NPM in the cytosol that does not depend on its ability to shuttle to and from the nucleus concerns the control of centrosome duplication. Anomalies in the centrosome cycle often cause aneuploidy, which is common in cancer. The finding that NPMc+ AML is associated with a normal karyotype may suggest that the mutated NPMc+ protein still functions normally at the centrosome.
Whatever its role in leukemogenesis may turn out to be, the identification of cytoplasmic NPM in a high proportion of cases of AML is an important finding, not only because it has clinical implications but also because it calls for further studies of the molecular basis of the role of NPM in oncogenesis.
Source Information
From the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York.
References
Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994;263:1281-1284.
Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996;87:882-886.
Yoneda-Kato N, Look AT, Kirstein MN, et al. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 1996;12:265-275.
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.
Ruggero D, Pandolfi PP. Does the ribosome translate cancer? Nat Rev Cancer 2003;3:179-192.
Okuda M, Horn HF, Tarapore P, et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 2000;103:127-140.
Kondo T, Minamino N, Nagamura-Inoue T, Matsumoto M, Taniguchi T. Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity. Oncogene 1997;15:1275-1281.
Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG. Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol 2002;4:529-533.
Bertwistle D, Sugimoto M, Sherr CJ. Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Mol Cell Biol 2004;24:985-996.(Silvia Grisendi, Ph.D., a)