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

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 Citing Articles via Google Scholar Google Scholar Articles by Marcucci, G. Articles by Bloomfield, C. D. Search for Related Content PubMed PubMed Citation Articles by Marcucci, G. Articles by Bloomfield, C. D.

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.

This article has been cited by other articles:

				P. Paschka, G. Marcucci, A. S. Ruppert, S. P. Whitman, K. Mrozek, K. Maharry, C. Langer, C. D. Baldus, W. Zhao, B. L. Powell, et al. Wilms' Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., October 1, 2008; 26(28): 4595 - 4602. [Abstract] [Full Text] [PDF]

				J. P. Radich Molecular Classification of Acute Myeloid Leukemia: Are We There Yet? J. Clin. Oncol., October 1, 2008; 26(28): 4539 - 4541. [Full Text] [PDF]

				C. Langer, M. D. Radmacher, A. S. Ruppert, S. P. Whitman, P. Paschka, K. Mrozek, C. D. Baldus, T. Vukosavljevic, C.-G. Liu, M. E. Ross, et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study Blood, June 1, 2008; 111(11): 5371 - 5379. [Abstract] [Full Text] [PDF]

				G. Marcucci, M. D. Radmacher, K. Maharry, K. Mrozek, A. S. Ruppert, P. Paschka, T. Vukosavljevic, S. P. Whitman, C. D. Baldus, C. Langer, et al. MicroRNA Expression in Cytogenetically Normal Acute Myeloid Leukemia N. Engl. J. Med., May 1, 2008; 358(18): 1919 - 1928. [Abstract] [Full Text] [PDF]

				S. Liu, Z. Liu, Z. Xie, J. Pang, J. Yu, E. Lehmann, L. Huynh, T. Vukosavljevic, M. Takeki, R. B. Klisovic, et al. Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-{kappa}B-dependent DNA methyltransferase activity in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2364 - 2373. [Abstract] [Full Text] [PDF]

				S. P. Whitman, A. S. Ruppert, M. D. Radmacher, K. Mrozek, P. Paschka, C. Langer, C. D. Baldus, J. Wen, F. Racke, B. L. Powell, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications Blood, February 1, 2008; 111(3): 1552 - 1559. [Abstract] [Full Text] [PDF]

				G. J.L. Kaspers and C. M. Zwaan Pediatric acute myeloid leukemia: towards high-quality cure of all patients Haematologica, November 1, 2007; 92(11): 1519 - 1532. [Abstract] [Full Text] [PDF]

				C. D. Baldus, P. Martus, T. Burmeister, S. Schwartz, N. Gokbuget, C. D. Bloomfield, D. Hoelzer, E. Thiel, and W. K. Hofmann Low ERG and BAALC Expression Identifies a New Subgroup of Adult Acute T-Lymphoblastic Leukemia With a Highly Favorable Outcome J. Clin. Oncol., August 20, 2007; 25(24): 3739 - 3745. [Abstract] [Full Text] [PDF]

				G. Marcucci, K. Maharry, S. P. Whitman, T. Vukosavljevic, P. Paschka, C. Langer, K. Mrozek, C. D. Baldus, A. J. Carroll, B. L. Powell, et al. High Expression Levels of the ETS-Related Gene, ERG, Predict Adverse Outcome and Improve Molecular Risk-Based Classification of Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., August 1, 2007; 25(22): 3337 - 3343. [Abstract] [Full Text] [PDF]

				S. P. Whitman, A. S. Ruppert, G. Marcucci, K. Mrozek, P. Paschka, C. Langer, C. D. Baldus, J. Wen, T. Vukosavljevic, B. L. Powell, et al. Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study Blood, June 15, 2007; 109(12): 5164 - 5167. [Abstract] [Full Text] [PDF]

				C. Slape, H. Hartung, Y.-W. Lin, J. Bies, L. Wolff, and P. D. Aplan Retroviral Insertional Mutagenesis Identifies Genes that Collaborate with NUP98-HOXD13 during Leukemic Transformation Cancer Res., June 1, 2007; 67(11): 5148 - 5155. [Abstract] [Full Text] [PDF]

				K. Mrozek, G. Marcucci, P. Paschka, S. P. Whitman, and C. D. Bloomfield Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood, January 15, 2007; 109(2): 431 - 448. [Abstract] [Full Text] [PDF]

				C. D. Baldus, T. Burmeister, P. Martus, S. Schwartz, N. Gokbuget, C. D. Bloomfield, D. Hoelzer, E. Thiel, and W. K. Hofmann High Expression of the ETS Transcription Factor ERG Predicts Adverse Outcome in Acute T-Lymphoblastic Leukemia in Adults J. Clin. Oncol., October 10, 2006; 24(29): 4714 - 4720. [Abstract] [Full Text] [PDF]

				M. D. Radmacher, G. Marcucci, A. S. Ruppert, K. Mrozek, S. P. Whitman, J. W. Vardiman, P. Paschka, T. Vukosavljevic, C. D. Baldus, J. E. Kolitz, et al. Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study Blood, September 1, 2006; 108(5): 1677 - 1683. [Abstract] [Full Text] [PDF]

				S. S. Farag, K. J. Archer, K. Mrozek, A. S. Ruppert, A. J. Carroll, J. W. Vardiman, M. J. Pettenati, M. R. Baer, M. B. Qumsiyeh, P. R. Koduru, et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461 Blood, July 1, 2006; 108(1): 63 - 73. [Abstract] [Full Text] [PDF]

				C. D. Bloomfield, K. Mrozek, and M. A. Caligiuri Cancer and Leukemia Group B Leukemia Correlative Science Committee: Major Accomplishments and Future Directions. Clin. Cancer Res., June 1, 2006; 12(11): 3564s - 3571s. [Abstract] [Full Text] [PDF]

				B. W. Parcells, A. K. Ikeda, T. Simms-Waldrip, T. B. Moore, and K. M. Sakamoto FMS-Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia Stem Cells, May 1, 2006; 24(5): 1174 - 1184. [Abstract] [Full Text] [PDF]

				K. Mrozek and C. D. Bloomfield Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia Hematology, January 1, 2006; 2006(1): 169 - 177. [Abstract] [Full Text] [PDF]