As noted, t (15; 17) (q22; ql2-21) is characteristic of acute promyelocytic leukemia. As a result of this translocation, the so-called PML gene (gene of promyelocytic leukemia), located on chromosome 15, is transferred to the long arm of chromosome 17 in the region where the a-receptor retinoic acid (RARa) gene is located.
The RARa gene (retinoic acid receptor a) belongs to a family of receptor genes (genes for steroid hormone receptors, estrogens, thyroid, vitamin D3), which are transcription factors that, in the presence of certain ligands, can either activate or suppress the transactivation of the necessary genes. The ligand for the RARa gene is retinoic acid. Normally, this gene is involved in the regulation of the differentiation of myeloid cells.
It has long been noted that retinoids play a key role in myeloid differentiation, since in vitamin A deficiency, both in humans and experimental animals, there are impaired hematopoiesis, and the administration of retinoids mainly stimulates granulocytopoiesis. Retinoids (all-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, etc.) are ligands of the nuclear receptor RARa, which is attached to DNA in regions of the binding of retinoic acid (RARE) only after heterodimerization with another retino receptor X (RXR).
In the absence of ligands (retinoids), the heterodimer binds to the corepressors SMRT and N.COR, which in turn are associated with the histone deacetylase-Sin3A complex, which leads to repression of the transcription of the required genes. Histone deacetylases inhibit the transcription mechanisms by attaching the DNA molecule to histones (compact DNA on histones). When retinoic acid binds to RARa, corepressors are exchanged for transcription coactivators, which are associated with histone acetylases, which leads to DNA detachment from histones and activation of the transcription of the necessary genes.
The genes regulated by RARa include genes of cell cycle regulators (cyclins, cyclin-dependent kinases), adhesion molecules (CD11b, CD18), interleukins, monocytic chemoattractant, colony-stimulating factors (G-CSF, IL-1, IL-8), colony-stimulating factors (monocytic CSF and G-CSF receptors), regulators of apoptosis and terminal cell division (transglutaminase II, bc12), coagulation factors (thrombomodulin, tissue factor, urokinase, tissue plasminogen activator, and their inhibitors), transcription factor genes (STAT, NOC, activator of plasminogen and their inhibitors), transcription factor genes (STAT, NOC, activator of plasminogen and their inhibitors), transcription factor genes (STAT, NOC, activator of plasminogen and their inhibitors); e RAR).