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Previous Volume 350:1605-1616 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), the presence or absence of recurrent cytogenetic aberrations is used to identify the appropriate therapy. However, the current classification system does not fully reflect the molecular heterogeneity of the disease, and treatment stratification is difficult, especially for patients with intermediate-risk AML with a normal karyotype.

Methods We used complementary-DNA microarrays to determine the levels of gene expression in peripheral-blood samples or bone marrow samples from 116 adults with AML (including 45 with a normal karyotype). We used unsupervised hierarchical clustering analysis to identify molecular subgroups with distinct gene-expression signatures. Using a training set of samples from 59 patients, we applied a novel supervised learning algorithm to devise a gene-expression–based clinical-outcome predictor, which we then tested using an independent validation group comprising the 57 remaining patients.

Results Unsupervised analysis identified new molecular subtypes of AML, including two prognostically relevant subgroups in AML with a normal karyotype. Using the supervised learning algorithm, we constructed an optimal 133-gene clinical-outcome predictor, which accurately predicted overall survival among patients in the independent validation group (P=0.006), including the subgroup of patients with AML with a normal karyotype (P=0.046). In multivariate analysis, the gene-expression predictor was a strong independent prognostic factor (odds ratio, 8.8; 95 percent confidence interval, 2.6 to 29.3; P<0.001).

Conclusions The use of gene-expression profiling improves the molecular classification of adult AML.

Source Information

From the Departments of Pathology (L.B., J.R.P.), Health Research and Policy (E.B., R.T.), and Statistics (E.B., R.T.), Stanford University, Stanford, Calif.; and the Department of Internal Medicine III, University of Ulm, Ulm, Germany (K.D., S.F., R.F.S., H.D.).

Address reprint requests to Dr. Pollack at the Department of Pathology, Stanford University, 269 Campus Dr., CCSR 3245A, Stanford, CA 94305, or at pollack1{at}stanford.edu.

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• Oh, D. S., Troester, M. A., Usary, J., Hu, Z., He, X., Fan, C., Wu, J., Carey, L. A., Perou, C. M. (2006). Estrogen-Regulated Genes Predict Survival in Hormone Receptor-Positive Breast Cancers. JCO 24: 1656-1664 [Abstract] [Full Text]  
• 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]  
• Lee, S., Chen, J., Zhou, G., Shi, R. Z., Bouffard, G. G., Kocherginsky, M., Ge, X., Sun, M., Jayathilaka, N., Kim, Y. C., Emmanuel, N., Bohlander, S. K., Minden, M., Kline, J., Ozer, O., Larson, R. A., LeBeau, M. M., Green, E. D., Trent, J., Karrison, T., Liu, P. P., Wang, S. M., Rowley, J. D. (2006). Gene expression profiles in acute myeloid leukemia with common translocations using SAGE. Proc. Natl. Acad. Sci. USA 103: 1030-1035 [Abstract] [Full Text]  
• Erkeland, S. J., Verhaak, R. G.W., Valk, P. J.M., Delwel, R., Lowenberg, B., Touw, I. P. (2006). Significance of Murine Retroviral Mutagenesis for Identification of Disease Genes in Human Acute Myeloid Leukemia. Cancer Res. 66: 622-626 [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]  
• Gallagher, R. E. (2005). Dueling mutations in normal karyotype AML. Blood 106: 3681-3682 [Full Text]  
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• 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]  
• Bullinger, L., Kurz, S., Dohner, K., Scholl, C., Frohling, S., Schlenk, R. F., Dohner, H., Pollack, J. R. (2005). Gene Expression Profiling Identifies Distinct Subclasses in Core Binding Factor Acute Myeloid Leukemia.. ASH ANNUAL MEETING ABSTRACTS 106: 673-673 [Abstract]  
• Marcucci, G., Radmacher, M. D., Ruppert, A. S., Mrozek, K., Kolitz, J. E., Whitman, S. P., Edwards, C. G., Vardiman, J. W., Caligiuri, M. A., Carroll, A. J., Larson, R. A., Bloomfield, C. D. (2005). Independent Validation of Prognostic Relevance of a Previously Reported Gene-Expression Signature in Acute Myeloid Leukemia (AML) with Normal Cytogenetics (NC): A Cancer and Leukemia Group B (CALGB) Study.. ASH ANNUAL MEETING ABSTRACTS 106: 755-755 [Abstract]  
• Bullinger, L., Bair, E., Kranz, R., Dohner, K., Frohling, S., Schlenk, R. F., Tibshirani, R., Dohner, H., Pollack, J. R. (2005). Prognostic Gene-Expression Signatures in Adult Acute Myeloid Leukemia with Normal Karyotype.. ASH ANNUAL MEETING ABSTRACTS 106: 756-756 [Abstract]  
• Tomic, V., Russwurm, S., Moller, E., Claus, R.A., Blaess, M., Brunkhorst, F., Bruegel, M., Bode, K., Bloos, F., Wippermann, J., Wahlers, T., Deigner, H.-P., Thiery, J., Reinhart, K., Bauer, M. (2005). Transcriptomic and Proteomic Patterns of Systemic Inflammation in On-Pump and Off-Pump Coronary Artery Bypass Grafting. Circulation 112: 2912-2920 [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]  
• Liu, H., Li, J., Wong, L. (2005). Use of extreme patient samples for outcome prediction from gene expression data. Bioinformatics 21: 3377-3384 [Abstract] [Full Text]  
• Tallman, M. S., Gilliland, D. G., Rowe, J. M. (2005). Drug therapy for acute myeloid leukemia. Blood 106: 1154-1163 [Abstract] [Full Text]  
• Haferlach, T., Kohlmann, A., Schnittger, S., Dugas, M., Hiddemann, W., Kern, W., Schoch, C. (2005). Global approach to the diagnosis of leukemia using gene expression profiling. Blood 106: 1189-1198 [Abstract] [Full Text]  
• 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]  
• Kittleson, M. M., Minhas, K. M., Irizarry, R. A., Ye, S. Q., Edness, G., Breton, E., Conte, J. V., Tomaselli, G., Garcia, J. G. N., Hare, J. M. (2005). Gene expression analysis of ischemic and nonischemic cardiomyopathy: shared and distinct genes in the development of heart failure. Physiol. Genomics 21: 299-307 [Abstract] [Full Text]  
• Liu, E. T. (2005). Mechanism-derived gene expression signatures and predictive biomarkers in clinical oncology. Proc. Natl. Acad. Sci. USA 102: 3531-3532 [Full Text]  
• Labrie, F., Luu-The, V., Calvo, E., Martel, C., Cloutier, J., Gauthier, S., Belleau, P., Morissette, J., Levesque, M.-H., Labrie, C. (2005). Tetrahydrogestrinone induces a genomic signature typical of a potent anabolic steroid. J Endocrinol 184: 427-433 [Abstract] [Full Text]  
• Falini, B., Mecucci, C., Tiacci, E., Alcalay, M., Rosati, R., Pasqualucci, L., La Starza, R., Diverio, D., Colombo, E., Santucci, A., Bigerna, B., Pacini, R., Pucciarini, A., Liso, A., Vignetti, M., Fazi, P., Meani, N., Pettirossi, V., Saglio, G., Mandelli, F., Lo-Coco, F., Pelicci, P.-G., Martelli, M. F., the GIMEMA Acute Leukemia Working Party, (2005). Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype. NEJM 352: 254-266 [Abstract] [Full Text]  
• Ballen, K. K., Hasserjian, R. P. (2005). Case 2-2005 - A 39-Year-Old Woman with Headache, Stiff Neck, and Photophobia. NEJM 352: 274-283 [Full Text]