Originally published as JCO Early Release 10.1200/JCO.2008.20.6110 on May 18 2009

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Prognostic Importance of MN1 Transcript Levels, and Biologic Insights From MN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

Christian Langer, Guido Marcucci, Kelsi B. Holland, Michael D. Radmacher, Kati Maharry, Peter Paschka, Susan P. Whitman, Krzysztof Mrózek, Claudia D. Baldus, Ravi Vij, Bayard L. Powell, Andrew J. Carroll, Jonathan E. Kolitz, Michael A. Caligiuri, Richard A. Larson, Clara D. Bloomfield

From the Division of Hematology and Oncology, Department of Internal Medicine, 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; Washington University School of Medicine, Siteman Cancer Center, St Louis, MO; University of Alabama at Birmingham, Birmingham, AL; North Shore University Hospital, Manhasset, NY; University of Chicago, Chicago, IL; and the Department of Hematology and Oncology, Charité University Hospital, Berlin, Germany.

Corresponding author: Guido Marcucci, MD, Division of Hematology and Oncology, Comprehensive Cancer Center, The Ohio State University, Suite A434 Starling-Loving Hall, 320 W 10th Avenue, Columbus, OH 43210; e-mail: guido.marcucci{at}osumc.edu.

Purpose To determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene– and microRNA–expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML).

Patients and Methods MN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials.

Results Higher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation.

Conclusion MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.

C.L. and G.M. contributed equally to this article.

Supported in part by Grants No. CA101140, CA114725, CA31946, CA33601, CA16058, CA77658, CA35279, CA03927, and CA41287 from the National Cancer Institute, Bethesda, MD, 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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