Changes

The RARA gene encodes one of the three main receptor subclasses for retinoic acid. Retinoic acid receptors bind as heterodimers to their target DNA when bound to their ligand (retinoic acid) and regulate gene expression in various biological processes including hematopoiesis. The RXR/RAR heterodimers bind to the DNA retinoic acid response elements (RARE). In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. Upon ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation of target genes ([https://www.uniprot.org/uniprot/P10276#function adapted from Uniprot description]).

The RARA gene encodes one of the three main receptor subclasses for retinoic acid. Retinoic acid receptors bind as heterodimers to their target DNA when bound to their ligand (retinoic acid) and regulate gene expression in various biological processes including hematopoiesis. The RXR/RAR heterodimers bind to the DNA retinoic acid response elements (RARE). In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. Upon ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation of target genes ([https://www.uniprot.org/uniprot/P10276#function adapted from Uniprot description]).

Acute Promyelocytic Leukemia (APL) is a subtype of Acute Myeloid Leukemia AML that is almost entirely caused by the t(15;17)q22;q11) translocation resulting in the PML-RARA fusion gene.  It is likely that the fusion genes with RARA can both activate normally repressed genes and repress normally active genes.  The Pml-Rara fusion protein interferes with the binding of the ligand retinoic acid with the normal retinoic acid receptor, thus converting the retinoic acid receptor and Pml-Rara fusion protein into a transcriptional activator, ultimately resulting in the inhibition of gene expression for hematopoietic differentiation and the maturation arrest of hematopoietic progenitors at the promyelocyte stage.  In addition, the Pml-Rara protein acts as a dominant repressor of the normal PML protein [2].

Acute Promyelocytic Leukemia (APL) is a subtype of Acute Myeloid Leukemia AML that is almost entirely caused by the t(15;17)q22;q11) translocation resulting in the PML-RARA fusion gene.  Unlike the normal retinoic acid receptor, the Pml-Rara protein does not respond to the ligand signal to induce transcription of genes, so the genes remain repressed, ultimately resulting in the inhibition of gene expression for hematopoietic differentiation and the maturation arrest of hematopoietic progenitors at the promyelocyte stage.  In addition, while the normal PML protein blocks proliferation and induces apoptosis in combination with other proteins, the Pml-Rara protein acts as a dominant repressor of the normal PML protein [2].

==Common Alteration Types==

==Common Alteration Types==