Transcriptional regulation in acute promyelocytic leukemia

It has been 10 years since the seminal discovery that a mutant form of a re tinoid acid receptor (RAR alpha) is associated with acute promyelocytic leu kemia (APL). This finding, coupled with the remarkable success of retinoic acid (RA), the natural ligand of RAR alpha, in the treatment of APL, has ma de APL a unique model system in the study of oncogenic conversion of transc ription factors in hematological malignancies. Indeed, subsequent basic and clinical studies showed that chromosomal translocation involving the RAR a lpha 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 di fferentiation pathways controlled by both RAR and their fusion partners. Ho wever, it was not until recently that the role of aberrant transcriptional regulation in the pathogenesis of APL was revealed. In this review, we summ arize the biochemical and biological mechanisms of transcriptional regulati on by mutant RARs and their corresponding wild-type fusion partner PML and PLZF. These studies have been instrumental in our understanding of the proc ess of leukemogenesis in general and have laid the scientific foundation fo r the novel concept of transcription therapy in the treatment of human canc er.