Originally published as JCO Early Release 10.1200/JCO.2005.03.6137 on November 7 2005

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Overexpression of the ETS-Related Gene, ERG, Predicts a Worse Outcome in Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study

From the Division of Hematology and Oncology, Department of Internal Medicine, and Division of Human Cancer Genetics, Department of Microbiology, Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; The Cancer and Leukemia Group B Statistical Center; Duke University Medical Center, Durham; Wake Forest University School of Medicine, Winston-Salem, NC; North Shore University Hospital, Manhasset; Roswell Park Cancer Institute, Buffalo, NY; University of Chicago, Chicago, IL; and University of Alabama at Birmingham, Birmingham, AL. C.D. Baldus is currently at Charité, Campus Benjamin Franklin, Medizinische Klinik III, Berlin, Germany.

Address reprint requests to Guido Marcucci, MD, The Ohio State University, The Comprehensive Cancer Center, A433B Starling-Loving Hall, 320 W 10th Ave, Columbus OH 43210; e-mail: marcucci-1{at}medctr.osu.edu

PURPOSE: To test the prognostic significance of ETS-related gene (ERG) expression in cytogenetically normal primary acute myeloid leukemia (AML).

PATIENTS AND METHODS: Pretreatment blood samples from 84 cytogenetically normal AML patients aged less than 60 years, who were characterized for BAALC expression, FLT3 internal tandem duplication (ITD), and MLL partial tandem duplication (PTD) and uniformly treated on Cancer and Leukemia Group B 9621 protocol, were analyzed for ERG expression by real-time reverse transcriptase polymerase chain reaction. Patients were divided into quartiles according to ERG levels and were compared for clinical outcome. High-density oligonucleotide arrays were used to identify genes differentially expressed between high and low ERG expressers.

RESULTS: With a median follow-up of 5.7 years, patients with the upper 25% of ERG expression values had a worse cumulative incidence of relapse (CIR; P < .001) and overall survival (OS; P = .011) than the remaining patients. In a multivariable analysis, high ERG expression (P < .001) and the presence of MLL PTD (P = .027) predicted worse CIR. With regard to OS, an interaction was observed between expression of ERG and BAALC (P = .013), with ERG overexpression predicting shorter survival only in low BAALC expressers (P = .002). ERG overexpression was an independent prognostic factor even when the unfavorable group of FLT3 ITD patients lacking an FLT3 wild-type allele was included. High ERG expression was associated with upregulation of 112 expressed-sequenced tags and named genes, many of which are involved in cell proliferation, differentiation, and apoptosis.

CONCLUSION: ERG overexpression in AML patients with normal cytogenetics predicts an adverse clinical outcome and seems to be associated with a specific molecular signature.

Supported by National Cancer Institute (Bethesda, MD) Grants No. CA101140, CA77658, CA102031, CA31946, CA09512, CA16058, and CA90469 and The Coleman Leukemia Research Foundation.

Both G.M. and C.D. Baldus contributed equally to this work.

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

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