Originally published as JCO Early Release 10.1200/JCO.2008.17.5554 on September 22 2008

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Prognostic Significance of, and Gene and MicroRNA Expression Signatures Associated With, CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leukemia With High-Risk Molecular Features: A Cancer and Leukemia Group B Study

Guido Marcucci, Kati Maharry, Michael D. Radmacher, Krzysztof Mrózek, Tamara Vukosavljevic, Peter Paschka, Susan P. Whitman, Christian Langer, Claudia D. Baldus, Chang-Gong Liu, Amy S. Ruppert, Bayard L. Powell, Andrew J. Carroll, Michael A. Caligiuri, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield

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; University of Alabama at Birmingham, Birmingham, AL; North Shore University Hospital, Manhasset, NY; University of Chicago, Chicago, IL; and Charité University Hospital, Berlin, Germany

Corresponding author: Guido Marcucci, MD, The Ohio State University, Comprehensive Cancer Center, A433B Starling-Loving Hall, 320 W 10th Ave, Columbus, OH 43210; e-mail: guido.marcucci{at}osumc.edu

Purpose To evaluate the prognostic significance of CEBPA mutations in the context of established molecular markers in cytogenetically normal (CN) acute myeloid leukemia (AML) and gain biologic insights into leukemogenesis of the CN-AML molecular high-risk subset (FLT3 internal tandem duplication [ITD] positive and/or NPM1 wild type) that has a significantly higher incidence of CEBPA mutations than the molecular low-risk subset (FLT3-ITD negative and NPM1 mutated).

Patients and Methods One hundred seventy-five adults age less than 60 years with untreated primary CN-AML were screened before treatment for CEBPA, FLT3, MLL, WT1, and NPM1 mutations and BAALC and ERG expression levels. Gene and microRNA (miRNA) expression profiles were obtained for the CN-AML molecular high-risk patients.

Results CEBPA mutations predicted better event-free (P = .007), disease-free (P = .014), and overall survival (P < .001) independently of other molecular and clinical prognosticators. Among patients with CEBPA mutations, 91% were in the CN-AML molecular high-risk group. Within this group, CEBPA mutations predicted better event-free (P < .001), disease-free (P = .004), and overall survival (P = .009) independently of other molecular and clinical characteristics and were associated with unique gene and miRNA expression profiles. The major features of these profiles were upregulation of genes (eg, GATA1, ZFPM1, EPOR, and GFI1B) and miRNAs (ie, the miR-181 family) involved in erythroid differentiation and downregulation of homeobox genes.

Conclusion Pretreatment testing for CEBPA mutations identifies CN-AML patients with different outcomes, particularly in the molecular high-risk group, thus improving molecular risk-based classification of this large cytogenetic subset of AML. The gene and miRNA expression profiling provided insights into leukemogenesis of the CN-AML molecular high-risk group, indicating that CEBPA mutations are associated with partial erythroid differentiation.

published online ahead of print at www.jco.org on September 22, 2008

Supported in part by Grants No. CA101140, CA77658, CA31946, CA09512, CA16058, CA98933, CA90469, CA96887, CA33601, and CA089341 from the National Cancer Institute, Bethesda, MD; the Ohio State University Targeted Investments in Excellence; and the Coleman Leukemia Research Foundation.

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

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