The PML-RARα Fusion Protein and Targeted Therapy for Acute Promyelocytic Leukemia

Abstract

Acute promyelocytic leukemia (APL) is an unique subtype of acute myeloid leukemia typically carrying a specific reciprocal chromosome translocation t(15;17) leading to the expression of a leukemia-generating fusion protein, PML-RARα. Nearly all de novo APL patients undergo disease remission when treated with all trans retinoic acid (ATRA) plus chemotherapy. APL patients that relapse following this type of therapy respond to As₂O₃ with disease remission once again. The mechanism of action of both ATRA and As₂O₃ appears to be by inducing granulocytic differentiation and this cellular differentiation seems to depend on PML-RARα proteolysis. ATRA treatment results in partial cleavage and complete degradation of PML-RARα protein in differentiation sensitive, but not in differentiation resistant APL cells. As₂O₃ treatment results in only complete degradation of PML-RARα protein in both ATRA-sensitive and -resistant APL cells. PML-RARα appears to cause leukemia by acting as a transcriptional repressor of RARα target genes and by inhibiting activity of transcription factor C/EBPα. Therefore, PML-RARα proteolysis induced by ATRA and As₂O₃ may play an important role in overcoming the repressive activity of PML-RARα and allowing cellular differentiation to proceed. This review will focus on the status of the PML-RARα fusion protein and its relationship to gene and differentiation induction as well as differentiation resistance of APL cells.

• PML-RARα fusion protein
• Targeted therapy
• APL
• Acute promyelocytic leukemia