Signaling-mediated abrogation of polycomb silencing activates PAX5 expression in t(8;21) AML. In B cells, the PAX5 promoter is active and robust transcription occurs. In myeloid precursors, the gene is not expressed, but is poised for transcription and repressed by polycomb-repressive complexes. In t(8;21) AML, this polycomb repression is relieved via activated MAP kinase signaling, potentially cooperating with so far uncharacterized transcription factors (TF). This leads to the chronic activation of MAPKAPK3, which in turn leads to the dissociation of polycomb complexes from the PAX5 promoter region, effective transcriptional elongation, and aberrant expression of PAX5.