Promyelocytic leukemia protein-Retinoic acid receptor alpha fusion protein (PML-RARA) (PML-RARA)

The Promyelocytic leukemia protein-Retinoic acid receptor alpha fusion protein (PML-RARA) is a chimeric oncoprotein resulting from the reciprocal translocation t(15;17)(q24;q21), which is the pathognomonic driver of Acute Promyelocytic Leukemia (APL) (Melnick & Licht, Blood, 1999). This fusion protein combines the Promyelocytic Leukemia (PML) protein with the Retinoic Acid Receptor Alpha (RARA), creating a constitutive transcriptional repressor that blocks myeloid differentiation at the promyelocyte stage (de Thé & Chen, Nat Rev Cancer, 2010). Arsenic trioxide (ATO), the active component of the oral formulation QTX-2101, directly targets the PML moiety of the fusion protein (Zhang et al., Science, 2010). Binding of arsenic to the B2 domain of PML induces SUMOylation and subsequent RNF4-mediated ubiquitination, leading to the proteasomal degradation of the PML-RARA protein (Lallemand-Breitenbach et al., Nat Cell Biol, 2008). This degradation restores normal PML nuclear body formation and relieves the transcriptional block, allowing for the terminal differentiation and apoptosis of leukemic cells (Lo-Coco et al., N Engl J Med, 2013).

Other names

PML-RARalphat(15;17) fusion proteinPML/RARAPromyelocytic leukemia-retinoic acid receptor alpha

Arsenic trioxide binds to the PML moiety of the PML-RARA fusion protein, inducing its degradation via the ubiquitin-proteasome pathway, which relieves the transcriptional block and promotes myeloid differentiation.