Aberrant Gene Expression of BAALC and ERG in Older [≥60 Years (y)] De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): A Cancer and Leukemia Group B (CALGB) Study.
Authors: Schwind Sebastian , Marcucci Guido , Maharry Kati , Mrózek Krzysztof , Radmacher Michael D. , Holland Kelsi B. , Becker Heiko , Whitman Susan P. , Wu Yue-Zhong , Baer Maria R , Powell Bayard L. , Carroll Andrew J. , Caligiuri Michael A. , Larson Richard A. , Bloomfield Clara D. 
Published: October 2019

Abstract
Abstract 214

BAALC & ERG are aberrantly expressed in younger (<60 y) adult CN-AML patients (pts), where expression levels of these genes are also associated with clinical outcome. Whether aberrant BAALC & ERG expression also occurs in older (≥60 y) CN-AML pts is unknown. To assess the BAALC & ERG expression levels in older CN-AML & their impact on outcome we studied pts ≥60 y (median age, 68 y; range 60–83) enrolled on cytarabine/daunorubicin-based protocols [CALGB 10201, 9720, 9420, 8923, 8525], with diagnostic blood samples available for quantitative RT-PCR analysis (n=158), that were also characterized for other molecular prognosticators (FLT3-ITD, FLT3-TKD, NPM1 & WT1 mutations). BAALC & ERG expression values were normalized to an internal control (ABL1), & the median gene expression value was used to define high & low expressers for BAALC & ERG. Gene (GEP) & microRNA (MEP) expression profiling were done using, respectively, Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays. At diagnosis, lower BAALC expression was associated with mutated NPM1 (P<.001) & low ERG expression (P<.001). Lower BAALC expressers had a higher complete remission rate (CR; 86% v 54%, P<.001) & longer disease-free (DFS; P=.006; 3y rates 19% v 12%) & overall survival (OS; P<.001; 3y 29% v 10%) than higher expressers. Lower ERG expression was associated with lower WBC (P=.005), % marrow (BM; P=.001) & blood (P<.001) blasts & absent FLT3-ITD (P<.001) & low BAALC expression (P<.001). Lower ERG expression also associated with longer DFS (P=.001; 3y 18% v 14%) & OS (P<.001; 3y 24% v 15%). In multivariable models (Table 1), low BAALC expression independently associated with CR & longer DFS. BAALC & ERG expression were the only factors associated with OS. Comparison of age-groups (60-69 y v ≥70 y; Table 2) showed BAALC expression had a stronger prognostic impact in ≥70 y pts; lower expression was associated with higher CR rates & longer DFS & OS. ERG expression had instead stronger prognostic impact in 60-69 y pts (Table 2); lower expression was associated with longer DFS & OS. GEP (482 probes) & MEP (22 probes) differentiated low from high BAALC expressers. Low BAALC expressers had down-regulation of stem cell markers (CD34, CD133) & unfavorable outcome predictors (HGF, MN1, CD200), & up-regulation of HOX genes & miR-10a & miR-10b. GEP (1554 probes) & MEP (11 probes) differentiating low from high ERG expressers showed low ERG expressers had down-regulation of DNMT3B & up-regulation of topoisomerase 1 (TOP1), which is associated with enhanced chemotherapy sensitivity. Among up-regulated microRNAs in low ERG expressers was miR-208a, which is predicted to target ERG. In conclusion, lower expression of both BAALC & ERG associated with better outcome in older CN-AML pts even in the context of other established prognostic molecular markers, but have different impact on age-groups. GEP & MEP provided novel information that may elucidate how differential expression levels of these genes contribute to leukemogenesis & aid in developing novel risk-adapted therapies.

Disclosures:
No relevant conflicts of interest to declare.