The naturally occurring retinoic acid isomers 13-cis-retinoic acid and all-trans-retinoic acid (ATRA) influence processes of morphogenesis and differentiation. The effect of retinoic acid is mediated via the retinoic acid receptors α, β and γ (RARα, RARβ, RARγ). In the absence of ligands, retinoic acid receptors repress transcription by binding to retinoic acid response elements on the DNA. The inhibition of transcription is mediated or reinforced by various protein complexes. RARα associates with the nuclear corepressor NCoR and a histone deacetylase. Retinoic acid induces a conformational change that leads to the binding of coactivators, e.g. the H3K27 demethylase UTX instead of the co-repressors.
Acute promyelocytic leukemias (APLs) are characterized by the accumulation of haematopoietic progenitor cells, the further differentiation of which is blocked at the promyelocyte level. In this form of leukemia one finds translocations in which the RARA gene coding for the retinoic acid receptor-α on chromosome 17q is usually affected. In more than 95% of cases, the reciprocal translocation t(15; 17) is observed, in which parts of the RARA gene fuse with sequences of the PMLgene (PML: promyelocytic leukemia) mapped on chromosome 15q21. As a result of this translocation, the PML-RARα fusion protein is created, which combines important domains of the two proteins. PML is the eponym for substructures of the cell nucleus, which are referred to as “PML-oncogenic domains (PODs)” or “nuclear bodies”. Nuclear bodies are involved in many processes in the cell nucleus, such as transcription, replication and silencing of genes. The translocation blocks the formation of nuclear bodies.
The oncogenic effects of the PML-RAR fusion protein are based on various mechanisms:
● The specificity of the DNA binding is changed.
● PML has dimerization domains, just like other translocation partners of RARα. The resulting homodimers have a higher affinity for corepressors and histone deacetylases.
● DNA methyl transferases (DNMT1 and DNMT3) and a repressing histone methyl transferase are recruited.
● After binding to the promoters of the target genes, the PML-RARα protein associates with the Polycomb 2/3/4 complex.
Overall, the repressive effect of the PML-RARα fusion protein is increased compared to the non-translocated RARα.