Gene expression analysis of BCR/ABLI-dependent transcriptional response reveals genes involved in negative enrichment for feedback regulation

Philadelphia (Ph) chromosome-positive leukemia is characterized by the BCR/ABLI fusion protein that affects a wide range of signal transduction pathways. The knowledge about its downstream target genes is, however, still quite limited. To identify novel BCR/ABLI-regulated genes we used global gene expression profiling of several Ph-positive and Ph-negative cell lines treated with imatinib. Following imatinib treatment, the Ph-positive cells showed decreased growth, viability, and reduced phosphorylation of BCR/ABLI and STAT5. In total, 142 genes were identified as being dependent on BCR/ABLI-mediated signaling, mainly including genes involved in signal transduction, e.g. the JAK/STAT, MAPK, TGFB, and insulin signaling pathways, and in regulation of metabolism. Interestingly, BCR/ABLI was found to activate several genes involved in negative feedback regulation (CISH, SOCS2, SOCS3, PIMI, DUSP6, and TNFAIP3), which may act to indirectly suppress the tumor promoting effects exerted by BCR/ABLI. In addition, several genes identified as deregulated upon BCR/ABLI expression could be assigned to the TGFB and NFkB signaling pathways, as well as to reflect the metabolic adjustments needed for rapidly growing cells. Apart from providing important pathogenetic insights into BCR/ABLI-mediated leukemogenesis, the present study also provides a number of pathways/individual genes that may provide attractive targets for future development of targeted therapies.