RARA
Primary Author(s)*
Brian Davis PhD
Synonyms
Retinoic Acid Receptor Alpha; RAR-Alpha;
Genomic Location
Cytoband: 17q21.2
Genomic Coordinates:
chr17:38,465,423-38,513,895(GRCh37/hg19)
chr17:40,309,171-40,357,643(GRCh38/hg38)
Cancer Category/Type
Based on the early French-American-British (FAB) classification, Acute Promyelocytic Leukaemia (APL) is one of the subtypes (M3) of Acute Myeloid Leukemia AML [1].
Acute Promyelocytic Leukemia (APL) with PML-RARA
Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms
The PML-RARA fusion is reported to be found in 5-15% of AML, may occur at any age, but predominantly in adult in mid-life [1, 2]. RARA fusion proteins behave as potent transcriptional repressors of retinoic acid signalling, 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, 2, 3, 4].
Gene Overview
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) 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].
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 [4]
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| X | X |
Internal Pages
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Acute Promyelocytic Leukemia (APL) with PML-RARA
Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms
External Links
Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.
EXAMPLES
TP53 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
TP53 by COSMIC - sequence information, expression, catalogue of mutations
TP53 by CIViC - general knowledge and evidence-based variant specific information
TP53 by IARC - TP53 database with reference sequences and mutational landscape
TP53 by St. Jude ProteinPaint mutational landscape and matched expression data.
TP53 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
TP53 by Cancer Index - gene, pathway, publication information matched to cancer type
TP53 by OncoKB - mutational landscape, mutation effect, variant classification
TP53 by My Cancer Genome - brief gene overview
TP53 by UniProt - protein and molecular structure and function
TP53 by Pfam - gene and protein structure and function information
TP53 by GeneCards - general gene information and summaries
GeneReviews - information on Li Fraumeni Syndrome
References
1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.
2. Schafer, E.S. . 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: 347-57. PMID 24720386 DOI: 10.1586/17474086.2014.903794
4. Ng C.H. and Chng W.J. (2017). Recent advances in acute promyelocytic leukaemia. F1000Res. 6:1273. PMID 28794865 DOI: 10.12688/f1000research.10736.1
Notes
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