ORIGINAL ARTICLE ICER expression inhibits leukemia phenotype and controls tumor progression

The inducible cyclic AMP (cAMP) early repressor (ICER) andcAMP response element-binding protein (CREB) are transcrip-tional regulators of the cAMP-mediated signaling pathway.CREB has been demonstrated to be upregulated in the majorityof childhood leukemias contributing to disease progression,whereas ICER, its endogenous repressor, was found to bedownregulated. Our research focus has been the function ofrestored ICER expression. ICER exogenously expressed in celllines decreases CREB protein level and induces a loweredclonogenic potential in vitro. It decreases the ability of HL60 toinvade the extramedullary sites and to promote bone marrowangiogenesis in nonobese diabetic–severe combined immuno-deficient mice, demonstrating its potential effects on tumorprogression. ICER represses the majority of 96 target genesupregulated by CREB. It binds CRE promoters and controlsgene expression restoring the normal regulation of majorcellular pathways. ICER is subjected to degradation through aconstitutively active form of the extracellular signal-regulatedprotein kinase, which drives it to the proteasome. We proposethat ICER is downregulated in HL60 to preserve CREB over-expression, which disrupts normal myelopoiesis and promotesblast proliferation. These findings define the function of ICERas a tumor suppressor in leukemia. Unbalanced CREB/ICERexpression needs to be considered a pathogenetic feature inleukemogenesis. The molecular characterization of this path-way could be useful for novel therapeutic strategies.Leukemia (2008) 22, 2217–2225; doi:10.1038/leu.2008.244;published online 11 September 2008Keywords: CREB; ICER; gene expression; protein degradation