Avian erythroleukemia: a model for corepressor function in cancer

Transcriptional regulation at the level of chromatin plays crucial roles du ring eukaryotic development and differentiation. A plethora of studies reve aled that the acetylation status of histones is controlled by multiprotein complexes containing (de)acetylase activities. In the current model, histon e deacetylases and acetyltransferases are recruited to chromatin by DNA-bou nd repressors and activators, respectively. Shifting the balance between de acetylation, i.e. repressive chromatin and acetylationl i.e. active chromat in can lead to aberrant gene transcription and cancer, In human acute promy elocytic leukemia (APL) and avian erythroleukemia (AEL), chromosomal transl ocations and/or mutations in nuclear hormone receptors, RAR alpha [NR1B1] a nd TR alpha [NR1A1], yielded oncoproteins that deregulate transcription and alter chromatin structure. The oncogenic receptors are locked in their 'of f' mode thereby constitutively repressing transcription of genes that are c ritical for differentiation of hematopoietic cells. AEL involves an oncogen ic version of the chicken TR alpha, v-ErbA, Apart from repression by v-ErbA , ia recruitment of corepressor compleses, other repressors and corepressor s appear to be involved in repression of v-ErbA target genes, such as carbo nic anhydrase II (CAII), Reactivation of repressed genes in APL and AEL by chromatin modifying agents such as inhibitors of histone deacetylase or of methylation provides nem therapeutic strategies in the treatment of acute m yeloid leukemia.