Overexpression of the ERG Gene Is an Adverse Prognostic Factor in Acute Myeloid Leukemia (AML) with Normal Cytogenetics (NC): A Cancer and Leukemia Group B Study (CALGB).

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Abstract
Around 45% of adults with AML have NC and are included in an intermediate-risk group. However, their 5-year (yr) overall survival (OS) rates vary between 24 and 42%, likely due to the prognostic impact of submicroscopic genetic alterations, e.g., mutations in FLT3, CEBPA, MLL and NPM genes and overexpression of BAALC. We recently showed that ERG, an ETS-Related Gene mapped to 21q22, is often overexpressed in AML with unfavorable complex karyotypes, and in a subset of NC AML ( When ERG expression was evaluated in the context of pts with known FLT3 internal tandem duplication (ITD) status, including those with the very unfavorable FLT3ITD/-genotype, i.e., lacking the FLT3 wild-type allele, a multivariable analysis showed that higher risk of relapse and death was independently predicted by both high ERG expression values (i.e., Q4) (P=.023 and P=.002, respectively) and FLT3 ITD mutations (P≤ .001 and P=.002, respectively). We also used Affymetrix U133 plus 2.0 GeneChips to identify genes differentially expressed (P≤ .001) between Q4 and Q1-3 pts. Q4 pts displayed a signature characterized by overexpression of 63 genes and 49 expressed-sequenced tags. Fourteen genes, including general (GTF2H2) and lineage-specific (BCL11A, HEMGN) transcription regulators and genes involved in cell proliferation (RAB10, GAS5) and apoptosis (IKIP, DAPK), had at least a two-fold difference in expression levels between the Q4 and Q1-3 groups. In conclusion, we show for the first time that ERG overexpression in NC AML constitutes an adverse prognostic factor and is associated with a distinct gene-expression signature.

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