Abstract 2717: Higher MN1 expression is an unfavorable prognosticator in older patients (Pts) with cytogenetically normal acute myeloid leukemia (CN-AML): A CALGB study
Authors: Schwind Sebastian , Marcucci Guido , Holland Kelsi B. , Mrózek Krzysztof , Michael Radmacher D. , Maharry Kati , Becker Heiko , Whitman Susan P. , Wu Yue-Zhong , Carter Thomas H. , Powell Bayard L. , Caligiuri Michael A. , Baer Maria R. , Larson Richard A. , Bloomfield Clara D. 
Published: February 2011

Abstract
In younger (&lt;60 y) adult CN-AML pts, high MN1 expression associates with adverse outcome. The prognostic impact of MN1 expression in older pts (&gt;60 y) requires further evaluation. Pre-therapy bone marrow samples from 140 older de novo CN-AML pts (median age 68 y; range 60 – 81 y) enrolled on cytarabine/daunorubicin-based protocols were studied centrally by RT-PCR. Using the median expression value for MN1, as a cutoff pts were grouped as high & low MN1 expressers. Analysis of the mutation status for FLT3-ITD, FLT3-TKD, NPM1, CEBPA & WT1 & gene & microRNA (miR) expression profiling using, respectively, Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays, were performed centrally. At diagnosis, higher MN1 associated with wild-type NPM1 (P&lt;.001). Median follow-up was 4.0 y for pts alive. High MN1 expressers had lower complete remission (CR; 53% v 80%, P=.001), shorter event-free (EFS; P=.004; 3y 6% v 14%) & overall survival (OS; P=.03; 3y 10% v 23%; Table) rates. In multivariable models, higher MN1 expression independently associated with a lower CR rate & shorter EFS. Comparison of age groups (60-69 y v ≥70 y) revealed that MN1 expression had a stronger prognostic impact on pts ≥70 y (n=61; Table). Gene (294 genes) & miR (21 miRs) expression signatures associated with high MN1 expression were derived. High MN1 pts had higher expression of precursor markers (CD34, PROM1, CD44, KIT, HLA-DRB1, DNTT), known adverse outcome predictors (BAALC, ERG, HGF), anti-apoptotic BCL2, & miR-101 & miR-126, which are linked to hematologic differentiation. Underexpressed were HOX genes, their co-regulators (MEIS1) & HOX-gene embedded miRs (miR-10a, miR-10b). In conclusion, higher MN1 associated with adverse outcome in older CN-AML pts independently of other established prognosticators & had a stronger impact on ≥70 y pts. The expression signatures provide novel information that may elucidate how MN1 contributes to leukemia & help design new therapeutic approaches.Table.Outcomes according to MN1 expression of all pts and, separately, those age 60-69 y and ≥70yOutcome End PointsMN1 expressionAll Pts (n=140)Pts age 60-69 y (n=79)Pts age ≥70 y (n=61)HighLowPHighLowPHighLowP% achieving CR5380.0015480.035181.03EFS, %event-free at 3 y614.00467.11627.007OS, %alive at 3 y1023.031118.44931.006 The clinical endpoints significantly associated with MN1 expression levels are denoted by bold type.Pts were enrolled on CALGB protocols [CALGB 8525, 8923, 9420, 9720 & 10201].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2717.