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Overexpression of the ETS-Related Gene

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Overexpression of the ETS-Related Gene VOLUME 23 ⅐ NUMBER 36 ⅐ DECEMBER 20 2005 JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT 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 Guido Marcucci, Claudia D. Baldus, Amy S. Ruppert, Michael D. Radmacher, Krzysztof Mro´zek, Susan P. Whitman, Jonathan E. Kolitz, Colin G. Edwards, James W. Vardiman, Bayard L. Powell, Maria R. Baer, Joseph O. Moore, Danilo Perrotti, Michael A. Caligiuri, Andrew J. Carroll, Richard A. Larson, Albert de la Chapelle, and Clara D. Bloomfield From the Division of Hematology and ABSTRACT Oncology, Department of Internal Medi- cine, and Division of Human Cancer Genetics, Department of Microbiology, Purpose Virology, Immunology, and Medical To test the prognostic significance of ETS-related gene (ERG) expression in cytogenetically Genetics, Comprehensive Cancer normal primary acute myeloid leukemia (AML). Center, The Ohio State University, Columbus, OH; The Cancer and Leuke- Patients and Methods mia Group B Statistical Center; Duke Pretreatment blood samples from 84 cytogenetically normal AML patients aged less than 60 University Medical Center, Durham; years, who were characterized for BAALC expression, FLT3 internal tandem duplication (ITD), Wake Forest University School of Medi- and MLL partial tandem duplication (PTD) and uniformly treated on Cancer and Leukemia Group cine, Winston-Salem, NC; North Shore B 9621 protocol, were analyzed for ERG expression by real-time reverse transcriptase polymer- University Hospital, Manhasset; Roswell ase chain reaction. Patients were divided into quartiles according to ERG levels and were Park Cancer Institute, Buffalo, NY; University of Chicago, Chicago, IL; and compared for clinical outcome. High-density oligonucleotide arrays were used to identify genes University of Alabama at Birmingham, differentially expressed between high and low ERG expressers. Birmingham, AL. C.D. Baldus is currently at Charité, Campus Benjamin Franklin, Results Medizinische Klinik III, Berlin, Germany. 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 Ͻ .001) and overall survival (OS; P ϭ .011) Submitted July 28, 2005; accepted Ͻ September 19, 2005. than the remaining patients. In a multivariable analysis, high ERG expression (P .001) and the presence of MLL PTD (P ϭ .027) predicted worse CIR. With regard to OS, an interaction was Supported by National Cancer Insti- observed between expression of ERG and BAALC (P ϭ .013), with ERG overexpression tute (Bethesda, MD) Grants No. ϭ CA101140, CA77658, CA102031, predicting shorter survival only in low BAALC expressers (P .002). ERG overexpression was an CA31946, CA09512, CA16058, and independent prognostic factor even when the unfavorable group of FLT3 ITD patients lacking an CA90469 and The Coleman Leukemia FLT3 wild-type allele was included. High ERG expression was associated with upregulation of Research Foundation. 112 expressed-sequenced tags and named genes, many of which are involved in cell prolifera- Both G.M. and C.D. Baldus contributed tion, differentiation, and apoptosis. equally to this work. Conclusion Authors’ disclosures of potential con- ERG overexpression in AML patients with normal cytogenetics predicts an adverse clinical flicts of interest are found at the end of outcome and seems to be associated with a specific molecular signature. this article. Address reprint requests to Guido J Clin Oncol 23:9234-9242. © 2005 by American Society of Clinical Oncology Marcucci, MD, The Ohio State Univer- sity, The Comprehensive Cancer Center, A433B Starling-Loving Hall, 320 togenetic subset of adult AML, approximately W 10th Ave, Columbus OH 43210; INTRODUCTION e-mail: [email protected]. 45%, consists of patients with a normal karyo- 1 © 2005 by American Society of Clinical Cytogenetic abnormalities detected at diag- type. In large studies of the clinical signifi- Oncology nosis have long been recognized as predic- cance of cytogenetics in AML, these patients 0732-183X/05/2336-9234/$20.00 tors for clinical outcome in acute myeloid have been categorized in an intermediate-risk DOI: 10.1200/JCO.2005.03.6137 leukemia (AML).1 However, the largest cy- group, with 5-year survival rates varying 9234 Information downloaded from jco.ascopubs.org and provided by at GEORGETOWN UNIVERSITY MEDICAL CENTE on Copyright © 2005September American 17,Society 2014 of from Clinical 141.161.133.132 Oncology. All rights reserved. ERG Expression and Prognosis in AML between 24% and 42%.2-5 The difference in clinical out- patients were enrolled onto the treatment trial CALGB 9621,28 the 29 come likely reflects molecular heterogeneity of this cytoge- prospective cytogenetic study CALGB 8461, and the molecular 15 netic subset whose prognosis is influenced by submicroscopic study of BAALC expression (CALGB 9665). Written institu- tional review board–approved informed consent was obtained gene mutations or overexpression.6 The adverse prognostic from all patients. impact of the partial tandem duplication (PTD) of MLL, Pretreatment cytogenetic analyses of bone marrow (BM) internal tandem duplication (ITD) of FLT3, and overex- were performed as previously described.4,30At least 20 met- pression of BAALC in karyotypically normal AML is now aphases were analyzed, and the karyotype was normal in each established,7-17 as is the favorable prognostic significance of case. Pretreatment MLL PTD and FLT3 ITD status and BAALC CEBPA gene mutations.17,18 However, it is likely that, in levels were also determined centrally for each patient, as de- 7,10,15 addition to the aforementioned genetic abnormalities, oth- scribed previously. ers will be found to impact on the clinical outcome of Treatment cytogenetically normal AML. Given that intensive treat- Patients received induction chemotherapy with cytarabine, ments such as allogeneic stem-cell transplantation (SCT), daunorubicin, and etoposide with valspodar (PSC-833) or with- 28 although potentially curative in patients with poor progno- out valspodar. On achievement of complete remission (CR), patients received high-dose etoposide and cytarabine for stem-cell sis AML, are associated with high treatment-related mortal- mobilization followed by myeloablative treatment with busulfan ity, novel molecular markers will likely be valuable to and etoposide supported by autologous peripheral-blood SCT stratify karyotypically normal AML patients to risk-adapted (APBSCT). Patients unable to receive APBSCT received two addi- therapies. Furthermore, because these markers are mutated tional cycles of high-dose cytarabine. After consolidation, patients or overexpressed genes encoding proteins with potentially received maintenance with interleukin-2. pivotal roles in leukemogenesis, they could also serve as RNA Extraction and Real-Time Reverse Transcriptase 19 molecular targets for novel therapeutic approaches. Polymerase Chain Reaction We have recently shown that ETS-related gene (ERG), ERG expression was measured in blood for consistency with which is located at chromosome band 21q22, is frequently our previous analysis of the same patients characterized for 15 overexpressed in AML patients with complex karyotypes BAALC expression. Mononuclear cells from pretreatment blood and cryptic amplification of chromosome 21.20 ERG and were enriched by Ficoll-Hypaque gradient and cryopreserved in liquid nitrogen. Samples were chosen based on the availability of other members of the ETS family are downstream effectors procured material with adequate RNA quality in the CALGB Leu- of mitogenic signaling transduction pathways and are in- kemia Tissue Bank. Total RNA was extracted using Trizol reagent volved in key steps regulating cell proliferation, differentia- (Invitrogen, Carlsbad, CA). cDNA synthesis and the real-time tion, and apoptosis.21-23 Although ERG rearrangements amplification reactions were performed as previously reported.15 24 25 have been found in AML and Ewing sarcoma and its The comparative cycle threshold (CT) method was used to overexpression has been observed in prostate cancer,26 little determine the relative expression levels of ERG to GPI, the internal control, in patients previously included in the BAALC expression is known regarding how ERG contributes to malignant 15 27 20 study. Of the original 86 patients, 84 were analyzed for ERG/GPI transformation. In our previous report, high ERG ex- ⌬ levels calculated using the mean of CT from two replicates and pression was not always associated with genomic amplifica- expressed as 2␮(⌬CT). The results of real-time reverse transcriptase tion, thereby leaving ERG overexpression mechanistically polymerase chain reaction (RT-PCR) were correlated with clinical unexplained. Nevertheless, the recurrent presence of ERG end points. overexpression in AML with complex karyotypes, a prog- To assess the impact of ERG levels on clinical outcome, we nostically unfavorable subgroup, suggests that ERG overex- also adopted an alternative approach. Absolute ERG copy num- pression might not only be a nonrandom event in myeloid bers were measured and normalized to the copy numbers of ABL, which was a different internal control validated by multicenter leukemogenesis, but also might contribute to an aggressive studies,31,32 using standard curves constructed as reported previ- malignant phenotype. ously.33 We analyzed 73 samples comprising 48 samples from To test this hypothesis, we analyzed karyotypically
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