Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) (PML-RARα)

Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) is a chimeric fusion protein resulting from the t(15;17)(q24;q21) reciprocal translocation, which is the hallmark of acute promyelocytic leukemia (APL) (Source: StatPearls). This fusion protein acts as a dominant-negative transcriptional repressor by binding to retinoic acid response elements (RAREs) and recruiting corepressor complexes, including SMRT (Silencing Mediator for Retinoid and Thyroid hormone receptors) and NCoR, which are associated with histone deacetylase (HDAC) activity (Source: PubMed 9566893). This recruitment leads to condensed chromatin and the silencing of genes required for myeloid differentiation, effectively halting leukocyte maturation at the promyelocytic stage. PML-RARα also disrupts the formation of PML nuclear bodies, which are involved in apoptosis and senescence (Source: UniProt P23528). Therapeutic management involves All-trans retinoic acid (ATRA), which binds the RARα domain to induce corepressor dissociation and promote differentiation, and arsenic trioxide (ATO), which binds the PML zinc finger domains to trigger SUMOylation and proteasomal degradation of the fusion protein (Source: Science 2010, 328(5975):240-243). The combination of these agents has transformed APL into a highly curable malignancy by directly targeting the molecular drivers of the disease.

Other names

PML-RARA fusion proteint(15;17) translocation proteinPML-RARalphaPML-RARα/SMRT complex

All-trans retinoic acid (ATRA) binds to the RARα portion of the PML-RARα fusion protein, inducing a conformational change that causes the dissociation of corepressors like SMRT and NCoR and the recruitment of coactivators, thereby restoring the transcription of genes necessary for myeloid differentiation (Source: StatPearls). Arsenic trioxide (ATO) directly binds to cysteine residues within the zinc finger domains (specifically the RING domain and B-box 2) of the PML moiety, which promotes the SUMOylation of the fusion protein and its subsequent degradation via the RNF4-mediated proteasomal pathway (Source: Science 2010, 328(5975):240-243).