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.