Transcriptional regulation in acute promyelocytic leukemia

It has been 10 years since the seminal discovery that a mutant form of a retinoid acid receptor (RAR alpha) is associated with acute promyelocytic leukemia (APL). This finding, coupled with the remarkable success of retinoic acid (RA), the natural ligand of RAR alpha, in the treatment of APL, has made APL a unique model system in the study of oncogenic conversion of transcription factors in hematological malignancies. Indeed, subsequent basic and clinical studies showed that chromosomal translocation involving the RAR alpha gene is the cytogenetic hallmark of APL and that these mutant forms of RARs are the oncogenes in APL that interfere with the proliferation and differentiation pathways controlled by both RAR and their fusion partners. However, it was not until recently that the role of aberrant transcriptional regulation in the pathogenesis of APL was revealed. In this review, we summarize the biochemical and biological mechanisms of transcriptional regulation by mutant RARs and their corresponding wild-type fusion partner PML and PLZF. These studies have been instrumental in our understanding of the process of leukemogenesis in general and have laid the scientific foundation for the novel concept of transcription therapy in the treatment of human cancer.