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Blood, 15 July 2006, Vol. 108, No. 2, pp. 685-696.
Prepublished online as a Blood First Edition Paper on April 4, 2006; DOI 10.1182/blood-2004-12-4633.
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NEOPLASIA
Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction
Carla S. Wilson,
George S. Davidson,
Shawn B. Martin,
Erik Andries,
Jeffrey Potter,
Richard Harvey,
Kerem Ar,
Yuexian Xu,
Kenneth J. Kopecky,
Donna P. Ankerst,
Holly Gundacker,
Marilyn L. Slovak,
Monica Mosquera-Caro,
I-Ming Chen,
Derek L. Stirewalt,
Maurice Murphy,
Frederick A. Schultz,
Huining Kang,
Xuefei Wang,
Jerald P. Radich,
Frederick R. Appelbaum,
Susan R. Atlas,
John Godwin, and
Cheryl L. Willman
From the Department of Pathology and the Cancer Research and Treatment Center, University of New Mexico (UNM), Albuquerque; Sandia National Laboratories, Albuquerque, NM; Departments of Computer Science, Mathematics and Statistics, and Physics and Astronomy, and the UNM Center for High Performance Computing, University of New Mexico, Albuquerque; Southwest Oncology Group Statistical Center, Seattle, WA; City of Hope National Medical Center, Duarte, CA; Fred Hutchinson Cancer Research Center, Seattle, WA; and Loyola University, Chicago, IL.
To determine whether gene expression profiling could improve risk classification and outcome prediction in older acute myeloid leukemia (AML) patients, expression profiles were obtained in pretreatment leukemic samples from 170 patients whose median age was 65 years. Unsupervised clustering methods were used to classify patients into 6 cluster groups (designated A to F) that varied significantly in rates of resistant disease (RD; P < .001), complete response (CR; P = .023), and disease-free survival (DFS; P = .023). Cluster A (n = 24), dominated by NPM1 mutations (78%), normal karyotypes (75%), and genes associated with signaling and apoptosis, had the best DFS (27%) and overall survival (OS; 25% at 5 years). Patients in clusters B (n = 22) and C (n = 31) had the worst OS (5% and 6%, respectively); cluster B was distinguished by the highest rate of RD (77%) and multidrug resistant gene expression (ABCG2, MDR1). Cluster D was characterized by a "proliferative" gene signature with the highest proportion of detectable cytogenetic abnormalities (76%; including 83% of all favorable and 34% of unfavorable karyotypes). Cluster F (n = 33) was dominated by monocytic leukemias (97% of cases), also showing increased NPM1 mutations (61%). These gene expression signatures provide insights into novel groups of AML not predicted by traditional studies that impact prognosis and potential therapy.
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