The Identification of ERG Related Pathways Pinpoints to Mechanisms Implicated in the Inferior Outcome of Acute T-Lymphoblastic Leukemia (T-ALL) with High ERG Expression.

The ETS transcription factor ERG is expressed during early, normal T-cell development and shut off once T-cell commitment is complete. In addition, ERG is involved in various chromosomal translocations and implicated in oncogenic pathways in Ewing sarcoma, prostate cancer, and acute myeloid leukemia. Due to the specific regulation during T-cell development and its oncogenic potential we investigated the prognostic impact of ERG expression in T-lymphoblastic leukemia (T-ALL). We have shown in a cohort of 105 adult patients (pts) with newly diagnosed T-ALL that high ERG expression is an independent risk factor predicting inferior relapse-free survival (RFS, P=0.003; 5-year RFS: high ERG 34% vs. low ERG 72%; Baldus et al., JCO. Vol. 24 10/2006). Gene expression profiling (Affymetrix U133 plus 2.0) was performed on diagnostic bone marrow samples of 31 adult T-ALL pts to define an ERG related gene expression signature indicative of its pathogenic role in T-ALL. ERG mRNA expression levels were determined by quantitative real-time RT-PCR and pts were dichotomized at ERG′s median expression level into low ERG (n=16) and high ERG expressers (n=15). After a filtering step that reduced the number of probe sets to just over 10,000, we identified 39 probe sets (representing 35 known genes) differentially expressed (P<0.001) between low ERG and high ERG expressers. Compared to the low ERG group, 23 probe sets had significantly higher expression levels in the high ERG group, and 16 probe sets had significantly lower expression levels in the high ERG group. This signature contained three probe sets for ERG, each one showing about a 2-fold higher expression in the high ERG group as compared to the low ERG group; supporting our RT-PCR results. Of the overexpressed genes in the high ERG group, 5 genes were involved in DNA binding (MYO18A, DNAJC1) or transcription factor activity (ERG, ETV6, DIP). ERG and ETV6 are both ETS transcription factors and are frequently rearranged resulting in oncogenic fusion genes involved in leukemia. Moreover, ETV6 has been shown to be essential for the establishment of early hematopoiesis. In addition, genes with ATPase and ATP binding activity (ATP2B4, ATP2C1, MYO18A), potentially involved in signal transduction pathways were related to high ERG expression. Up-regulation of AKR1C1, a member of the aldo-keto reductase superfamily, was demonstrated in the high ERG group. Interestingly, overexpression of AKR1C1 has been found in various types of cancers and was correlated with tumor progression and resistance to chemotherapy. In conclusion, an ERG associated gene expression signature was identified in T-ALL and provides insights into ERG co-regulated genes. The delineation of these ERG related pathways may pinpoint mechanisms responsible for the more malignant phenotype resulting in the inferior outcome of T-ALL with high ERG expression.