Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia
Here we show that pan-haematopoietic ERG expression driven by the Vav promoter induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and human AML with high ERG expression. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel enhancer element validated in transgenic mice, and Pim1 inhibition disrupts growth and induces apoptosis of ERG-driven leukemic cells.  In addition, ERG indirectly induces the RAS pathway and direct RAS inhibition by a RAS inhibitor blocks growth of leukemia cells in vitro and in vivo. Thus, integrative genomic analysis of transgenic ERG leukemias reveals mechanisms and potential therapeutic targets of high ERG expressing AML. Overall design: Spleen cells were fixed with 1% formaldehyde and ChIP assays were performed as previously described (Wilson NK et al., 2010 Cell Stem Cell) using polyclonal antibodies against ERG-1/2/3 (clone C-17, Sc354X, Santa Cruz) and control nonspecific rabbit IgG (I5006, Sigma).