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Previous Volume 350:1617-1628 April 15, 2004 Number 16 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Perspective by Liu, E. T. Editorial by Grimwade, D. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background In patients with acute myeloid leukemia (AML) a combination of methods must be used to classify the disease, make therapeutic decisions, and determine the prognosis. However, this combined approach provides correct therapeutic and prognostic information in only 50 percent of cases.

Methods We determined the gene-expression profiles in samples of peripheral blood or bone marrow from 285 patients with AML using Affymetrix U133A GeneChips containing approximately 13,000 unique genes or expression-signature tags. Data analyses were carried out with Omniviz, significance analysis of microarrays, and prediction analysis of microarrays software. Statistical analyses were performed to determine the prognostic significance of cases of AML with specific molecular signatures.

Results Unsupervised cluster analyses identified 16 groups of patients with AML on the basis of molecular signatures. We identified the genes that defined these clusters and determined the minimal numbers of genes needed to identify prognostically important clusters with a high degree of accuracy. The clustering was driven by the presence of chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We identified several novel clusters, some consisting of specimens with normal karyotypes. A unique cluster with a distinctive gene-expression signature included cases of AML with a poor treatment outcome.

Conclusions Gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis.

Source Information

From the Departments of Hematology (P.J.M.V., R.G.W.V., M.A.B., C.A.J.E., S.B.W.D.-K., B.L., R.D.), Clinical Genetics (H.B.B.), and Bioinformatics (M.J.M., P.J.S.), Erasmus University Medical Center, Rotterdam; and the Leiden Genome Technology Center and the Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden (J.M.B.) — both in the Netherlands.

Address reprint requests to Dr. Valk at Erasmus University Medical Center Rotterdam, Department of Hematology, Ee13, Dr. Molewaterplein 50, 3015 GE Rotterdam Z-H, the Netherlands, or at p.valk{at}erasmusmc.nl.

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• Pasqualucci, L., Liso, A., Martelli, M. P., Bolli, N., Pacini, R., Tabarrini, A., Carini, M., Bigerna, B., Pucciarini, A., Mannucci, R., Nicoletti, I., Tiacci, E., Meloni, G., Specchia, G., Cantore, N., Di Raimondo, F., Pileri, S., Mecucci, C., Mandelli, F., Martelli, M. F., Falini, B. (2006). Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: impact on WHO classification. Blood 108: 4146-4155 [Abstract] [Full Text]  
• Greiner, J., Schmitt, M., Li, L., Giannopoulos, K., Bosch, K., Schmitt, A., Dohner, K., Schlenk, R. F., Pollack, J. R., Dohner, H., Bullinger, L. (2006). Expression of tumor-associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches. Blood 108: 4109-4117 [Abstract] [Full Text]  
• Heilman, S. A., Kuo, Y.-H., Goudswaard, C. S., Valk, P. J., Castilla, L. H. (2006). Cbf{beta} Reduces Cbf{beta}-SMMHC-Associated Acute Myeloid Leukemia in Mice. Cancer Res. 66: 11214-11218 [Abstract] [Full Text]  
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• Zhan, F., Huang, Y., Colla, S., Stewart, J. P., Hanamura, I., Gupta, S., Epstein, J., Yaccoby, S., Sawyer, J., Burington, B., Anaissie, E., Hollmig, K., Pineda-Roman, M., Tricot, G., van Rhee, F., Walker, R., Zangari, M., Crowley, J., Barlogie, B., Shaughnessy, J. D. Jr (2006). The molecular classification of multiple myeloma. Blood 108: 2020-2028 [Abstract] [Full Text]  
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• Wunderlich, M., Krejci, O., Wei, J., Mulloy, J. C. (2006). Human CD34+ cells expressing the inv(16) fusion protein exhibit a myelomonocytic phenotype with greatly enhanced proliferative ability. Blood 108: 1690-1697 [Abstract] [Full Text]  
• Radmacher, M. D., Marcucci, G., Ruppert, A. S., Mrozek, K., Whitman, S. P., Vardiman, J. W., Paschka, P., Vukosavljevic, T., Baldus, C. D., Kolitz, J. E., Caligiuri, M. A., Larson, R. A., Bloomfield, C. D. (2006). Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study. Blood 108: 1677-1683 [Abstract] [Full Text]  
• Brown, A. L., Wilkinson, C. R., Waterman, S. R., Kok, C. H., Salerno, D. G., Diakiw, S. M., Reynolds, B., Scott, H. S., Tsykin, A., Glonek, G. F., Goodall, G. J., Solomon, P. J., Gonda, T. J., D'Andrea, R. J. (2006). Genetic regulators of myelopoiesis and leukemic signaling identified by gene profiling and linear modeling. J. Leukoc. Biol. 80: 433-447 [Abstract] [Full Text]  
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• Wilson, C. S., Davidson, G. S., Martin, S. B., Andries, E., Potter, J., Harvey, R., Ar, K., Xu, Y., Kopecky, K. J., Ankerst, D. P., Gundacker, H., Slovak, M. L., Mosquera-Caro, M., Chen, I-M., Stirewalt, D. L., Murphy, M., Schultz, F. A., Kang, H., Wang, X., Radich, J. P., Appelbaum, F. R., Atlas, S. R., Godwin, J., Willman, C. L. (2006). Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction. Blood 108: 685-696 [Abstract] [Full Text]  
• Takeda, A., Goolsby, C., Yaseen, N. R. (2006). NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells.. Cancer Res. 66: 6628-6637 [Abstract] [Full Text]  
• Monzo, M., Brunet, S., Urbano-Ispizua, A., Navarro, A., Perea, G., Esteve, J., Artells, R., Granell, M., Berlanga, J., Ribera, J. M., Bueno, J., Llorente, A., Guardia, R., Tormo, M., Torres, P., Nomdedeu, J. F., Montserrat, E., Sierra, J., for CETLAM, (2006). Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia. Blood 107: 4871-4879 [Abstract] [Full Text]  
• Bloomfield, C. D., Mrozek, K., Caligiuri, M. A. (2006). Cancer and Leukemia Group B Leukemia Correlative Science Committee: Major Accomplishments and Future Directions.. Clin. Cancer Res. 12: 3564s-3571s [Abstract] [Full Text]  
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• Baldus, C. D., Thiede, C., Soucek, S., Bloomfield, C. D., Thiel, E., Ehninger, G. (2006). BAALC Expression and FLT3 Internal Tandem Duplication Mutations in Acute Myeloid Leukemia Patients With Normal Cytogenetics: Prognostic Implications. JCO 24: 790-797 [Abstract] [Full Text]  
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• Pitarch, A., Jimenez, A., Nombela, C., Gil, C. (2006). Decoding Serological Response to Candida Cell Wall Immunome into Novel Diagnostic, Prognostic, and Therapeutic Candidates for Systemic Candidiasis by Proteomic and Bioinformatic Analyses. Mol. Cell. Proteomics 5: 79-96 [Abstract] [Full Text]  
• Mrozek, K., Bloomfield, C. D. (2006). Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia. ASH Education Book 2006: 169-177 [Abstract] [Full Text]  
• Andersson, A., Olofsson, T., Lindgren, D., Nilsson, B., Ritz, C., Eden, P., Lassen, C., Rade, J., Fontes, M., Morse, H., Heldrup, J., Behrendtz, M., Mitelman, F., Hoglund, M., Johansson, B., Fioretos, T. (2005). Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations. Proc. Natl. Acad. Sci. USA 102: 19069-19074 [Abstract] [Full Text]  
• Gielen, S C J P, Kuhne, L C M, Ewing, P C, Blok, L J, Burger, C W (2005). Tamoxifen treatment for breast cancer enforces a distinct gene-expression profile on the human endometrium: an exploratory study. Endocr Relat Cancer 12: 1037-1049 [Abstract] [Full Text]  
• 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]  
• Tomlins, S. A., Rhodes, D. R., Perner, S., Dhanasekaran, S. M., Mehra, R., Sun, X.-W., Varambally, S., Cao, X., Tchinda, J., Kuefer, R., Lee, C., Montie, J. E., Shah, R. B., Pienta, K. J., Rubin, M. A., Chinnaiyan, A. M. (2005). Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer. Science 310: 644-648 [Abstract] [Full Text]  
• Paz-Priel, I., Cai, D. H., Wang, D., Kowalski, J., Blackford, A., Liu, H., Heckman, C. A., Gombart, A. F., Koeffler, H. P., Boxer, L. M., Friedman, A. D. (2005). CCAAT/Enhancer Binding Protein {alpha} (C/EBP{alpha}) and C/EBP{alpha} Myeloid Oncoproteins Induce Bcl-2 via Interaction of Their Basic Regions with Nuclear Factor-{kappa}B p50. Mol Cancer Res 3: 585-596 [Abstract] [Full Text]  
• Bullinger, L., Valk, P. J.M. (2005). Gene Expression Profiling in Acute Myeloid Leukemia. JCO 23: 6296-6305 [Abstract] [Full Text]  
• Marcucci, G., Mrozek, K., Ruppert, A. S., Maharry, K., Kolitz, J. E., Moore, J. O., Mayer, R. J., Pettenati, M. J., Powell, B. L., Edwards, C. G., Sterling, L. J., Vardiman, J. W., Schiffer, C. A., Carroll, A. J., Larson, R. A., Bloomfield, C. D. (2005). Prognostic Factors and Outcome of Core Binding Factor Acute Myeloid Leukemia Patients With t(8;21) Differ From Those of Patients With inv(16): A Cancer and Leukemia Group B Study. JCO 23: 5705-5717 [Abstract] [Full Text]  
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• 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]