Brian Davis PhD
Retinoic Acid Receptor Alpha; RAR-Alpha; RAR; NR1B1
Based on the early French-American-British (FAB) classification, Acute Promyelocytic Leukaemia (APL) is one of the subtypes (M3) of Acute Myeloid Leukemia AML . The PML-RARA fusion is reportedly found in 5-15% of AML and occurs at any age but predominantly in adults in mid-life [1,2]. RARA fusion proteins behave as potent transcriptional repressors of retinoic acid signaling, inducing a differentiation blockage at the promyelocyte stage which can be overcome with therapeutic doses of all-trans retinoic acid (ATRA) or arsenic trioxide [1-5]. ATO (arsenic trioxide) also induces differentiation of the malignant myeloid clone by dissociating the PML/RAR-alpha-RXR complex from the target genes and was found to have a synergistic action with ATRA .
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 (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) 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 .
Common Alteration Types
The translocation involving PML and RARA are found in more than 90% of cases of APL. Other fusion partners to RARA found in APL include PZLF, NPM1, NUMA1, STAT5B and BCOR. These rarer fusion genes account for around 5% of the total found in APL. Patients with these different fusion genes show different clinical responses to ATRA treatment. PZLF-RARA and STAT5b-RARA cases were refractory to ATRA, whereas NPM-RARA and NuMA-RARA were reported to be responsive. BCOR-RARA was also responsive to ATRA but carries a higher risk of relapse .
|Copy Number Loss||Copy Number Gain||LOH||Loss-of-Function Mutation||Gain-of-Function Mutation||Translocation/Fusion|
RARA by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
RARA by COSMIC - sequence information, expression, catalogue of mutations
RARA by CIViC - general knowledge and evidence-based variant specific information
RARA by St. Jude ProteinPaint mutational landscape and matched expression data.
RARA by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
RARA by Cancer Index - gene, pathway, publication information matched to cancer type
RARA by OncoKB - mutational landscape, mutation effect, variant classification
RARA by My Cancer Genome - brief gene overview
RARA by UniProt - protein and molecular structure and function
RARA by Pfam - gene and protein structure and function information
RARA by GeneCards - general gene information and summaries
RARA by NCBI - general gene information and summaries
RARA by OMIM - compendium of human genes and genetic phenotypes
RARA by LOVD(3) - Leiden Open Variation Database
RARA by TICdb - database of Translocation breakpoints In Cancer
1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p134-136.
2. Schafer ES, et al., (2015). Molecular Genetics of Acute Lymphoblastic Leukemia in The Molecular Basis of Cancer, 4th edition. Mendelsohn, J, Howley, PM, Israel, MA, Gray, JW, Thompson, CB. Editors. Elsevier Press: Philadelphia, USA, p395-406.
3. DeBraekeleer E, (2014). RARA fusion genes in acute promyelocytic leukemia: a review. Expert Rev Hematol 7: 347-357, PMID 24720386. DOI: 10.1586/17474086.2014.903794.
4. Ng CH and Chng WJ, (2017). Recent advances in acute promyelocytic leukaemia. F1000Res 6:1273, PMID 28794865. DOI: 10.12688/f1000research.10736.1.
5. Cingam SR and Koshy NV, (2017). Cancer, Leukemia, Promyelocytic, Acute (APL, APML). https://www.ncbi.nlm.nih.gov/books/NBK459352/.
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