Prognostic Importance of MN 1 Transcript Levels , and Biologic Insights From MN 1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia : A Cancer and Leukemia Group B Study

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. Geneand 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. Geneand 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 geneand microRNAexpression signatures suggest biologic features that could be exploited as therapeutic targets. J Clin Oncol 27:3198-3204. © 2009 by American Society of Clinical Oncology