Originally published as JCO Early Release 10.1200/JCO.2009.22.2547 on October 26 2009

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Rao, A. V. Articles by Löwenberg, B. PubMed PubMed Citation Articles by Rao, A. V. Articles by Löwenberg, B. Social Bookmarking                            What's this?

Age-Specific Differences in Oncogenic Pathway Dysregulation and Anthracycline Sensitivity in Patients With Acute Myeloid Leukemia

From the Division of Medical Oncology, Department of Medicine, Duke University Medical Center; and the Institute for Genomic Sciences and Policy, Duke University, Durham, NC; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands; and the Laboratory of Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilians-Universität-Campus Grobhadern, Munich, Germany.

Corresponding author: Arati V. Rao, MD, Duke Institute for Genome Sciences and Policy, Division of Medical Oncology, Box # 3382, 101 Science Dr, Duke University, Durham, NC 27708; e-mail: rao00012{at}mc.duke.edu.

Purpose To define the biology driving the aggressive nature of acute myeloid leukemia (AML) in elderly patients.

Patients and Methods Clinically annotated microarray data from 425 patients with newly diagnosed de novo AML from two publicly available data sets were analyzed after age-specific cohorts (young 45 years, n = 175; elderly 55 years; n = 144) were prospectively identified. Gene expression analysis was conducted utilizing gene set enrichment analysis, and by applying previously defined and tested signature profiles reflecting dysregulation of oncogenic signaling pathways, altered tumor environment, and signatures of chemotherapy sensitivity.

Results Elderly AML patients as expected had worse overall survival and event-free survival compared with younger patients. Analysis of oncogenic pathways revealed that older patients had higher probability of RAS, Src, and tumor necrosis factor (TNF) pathway activation (all P < .0001). Older patients were also less sensitive to anthracycline compared with younger patients with AML (P < .0001). Hierarchical clustering revealed that younger AML patients in cluster 2 had clinically worse survival, with high RAS, Src, and TNF pathway activation and in turn were less sensitive to anthracycline compared with patients in cluster 1. However, among elderly patients with AML, those in cluster 1 also demonstrated high RAS, Src, and TNF pathway activation but this did not translate into differences in survival or anthracycline sensitivity.

Conclusion AML in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathway variations that contributes to poor survival and anthracycline resistance. These insights should enable development and adjustments of clinically meaningful treatment strategies in the older patient population.

Supported in part by National Genome Research Network Plus Grant No. 01GS0876 from the German Ministry of Education and Research (S.K.B., C.B.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				H. Dohner, E. H. Estey, S. Amadori, F. R. Appelbaum, T. Buchner, A. K. Burnett, H. Dombret, P. Fenaux, D. Grimwade, R. A. Larson, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet Blood, January 21, 2010; 115(3): 453 - 474. [Abstract] [Full Text] [PDF]