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

The Promyelocytic leukemia–retinoic acid receptor alpha (PML-RARA) fusion protein is the primary oncogenic driver of acute promyelocytic leukemia (APL), typically resulting from a reciprocal translocation between chromosomes 15 and 17 [1]. This chimeric protein combines the N-terminus of the Promyelocytic Leukemia (PML) protein with the C-terminus of the Retinoic Acid Receptor Alpha (RARA) [2]. Functionally, PML-RARA acts as a dominant-negative transcriptional repressor that binds to retinoic acid response elements, recruiting histone deacetylases and corepressors to block the expression of genes essential for myeloid differentiation [3]. This blockade leads to the arrest of hematopoietic cells at the promyelocyte stage, causing their malignant accumulation in the bone marrow [4]. Therapeutic strategies specifically target the fusion protein; all-trans retinoic acid (ATRA) binds the RARA domain, while arsenic trioxide (ATO) binds the PML domain [5]. These interactions induce conformational changes that trigger the degradation of the fusion protein through the proteasome and autophagy pathways [6]. The degradation of PML-RARA relieves transcriptional repression and restores the normal differentiation program of the leukemic cells, leading to clinical remission [7]. Additionally, ATO promotes the reformation of PML nuclear bodies, which are disrupted by the fusion protein, further supporting tumor suppression [4].

Other names

PML-RARαt(15;17) fusion proteinPML/RARAPromyelocytic leukemia protein/Retinoic acid receptor alpha

Induction of proteasomal and autophagic degradation of the PML-RARA fusion protein, which relieves transcriptional repression and promotes terminal myeloid differentiation [5, 6].