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

The Promyelocytic leukemia protein-Retinoic acid receptor alpha fusion protein (PML-RARα) is a chimeric oncoprotein resulting from the t(15;17)(q24;q21) chromosomal translocation, which is the defining genetic hallmark of Acute Promyelocytic Leukemia (APL) [1, 2]. This fusion protein acts as a dominant-negative transcriptional repressor, blocking myeloid differentiation at the promyelocyte stage by recruiting corepressors and histone deacetylases to retinoic acid response elements (RAREs) [2, 5]. Arsenic trioxide (ATO) is a highly effective therapeutic agent that specifically targets the cysteine-rich zinc-binding domains, particularly the B-box2 domain, within the PML portion of the fusion protein [1, 4]. Binding of arsenic to these cysteine residues induces the multimerization and SUMOylation of PML-RARα, which subsequently triggers its degradation via the RNF4-mediated ubiquitin-proteasome pathway [1, 2]. This degradation leads to the restoration of normal PML nuclear bodies and allows for the resumption of cell differentiation and apoptosis, effectively eradicating the leukemic clones [1, 2]. Beyond its interaction with PML-RARα, arsenic also binds to other thiol-containing cellular proteins and enzymes, such as thioredoxin reductase, contributing to its broader cytotoxic and pro-oxidant effects in various cell types [3, 4].

Other names

PML-RARAPML/RARalphat(15;17) fusion proteinPromyelocytic leukemia-Retinoic acid receptor alphaCysteine-rich proteinsThiol-containing cellular proteins

Arsenic trioxide binds to cysteine residues in the B-box2 domain of the PML moiety, inducing multimerization, SUMOylation, and subsequent proteasomal degradation of the fusion protein [1, 2]. Tretinoin (ATRA) binds to the RARα moiety, inducing a conformational change that releases corepressors and recruits coactivators, promoting differentiation [2, 5].