Pml/rara as the master driver of apl pathogenesis and therapy response

Abstract

Acute promyelocytic leukemia (APL) is a model disease for targeted therapy. APL is caused by a variety of fusion proteins, all implicating the retinoic acid receptor alpha (RARA). The promyelocytic gene (PML)/RARA fusion is by far the most frequent, present in 99 % of patients. Two unconventional drugs, retinoic acid (RA) and arsenic trioxide were first shown to exhibit extraordinary clinical activity and later found to directly target PML/RARA. RA binds PML/RARA via its RARA moiety, activates transcription and degrades PML/RARA. Arsenic only degrades the fusion protein by targeting its PML part. Mouse modeling in APL has allowed an unprecedented level of understanding of the disease pathogenesis and basis for therapy response, highlighting the key role of PML/RARA degradation in the latter. The combination of RA and arsenic definitively eradicate the disease in mice and in most patients. APL thus represents a paradigm for oncoprotein-targeted cures.