RARA (Retinoic acid receptor, alpha)

2020-03-01 Franck Vigué Affiliation

Identity

HGNC

RARA

LOCATION

17q21.2

IMAGE

LEGEND

c-RARA (17q21) in normal cells: PAC 833D9 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

IMAGE

LEGEND

RARA (Retinoic acid receptor, alpha) Hybridization with LSI RARA Dual Color, Break Apart Rearrangement Probe (Abbott Molecular, US), showing the RARA gene on 17q21.2 (red-green or a fused yellow signal - Courtesy Adriana Zamecnikova.

LOCUSID

5914

ALIAS

NR1B1,RAR

FUSION GENES

Show Gene Fusions

Abstract

Review on RARA with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Description

9 exons; total gene sequence: 7450 bp.

Transcription

2.8 and 3.6 kb transcripts.

Proteins

RARA protein and domains.

Description

462 amino acids - 6 evolutionarily conserved domains - 5 functional domains : N-terminal A/B domain (transcriptional regulation AF1), C (DNA binding domain, contains 2 zinc fingers motifs, necessary for binding to RARE DNA sequence), D (cellular localization signal), E (ligand-binding domain, transcriptional regulation AF2) and F (function not well understood today)..

Expression

RARA is expressed in hematopoietic cells.

Localisation

Nuclear localisation.

Retinoid structures.

Function

Ligand-dependent transcription factor activated by all-trans retinoic acid (ATRA), specifically involved in hematopoietic stem cells differentiation and maturation = receptor for all-trans retinoic acid (ATRA) and 9-cis RA which are intracellular metabolites of vitamine A, active in cellular differentiation and morphogenesis. The gene response to RARA binding is modulated by a series of co-repressors and co-activators.
Retinol (vitamin A) is strictly furnished by the nutrition. The active retinol product is the retinoic acid (RA) which plays a great role as modulator of proliferation and differentiation in numerous tissues. In target cells retinol is oxidized as retinal with the help of an alcohol dehydrogenase. Then retinal is oxidized as ATRA by a retinal dehydrogenase (ALDH1A2 or RALDH). ATRA gives rise to 9-cis-RA, 11-cis-RA and 13-cis-RA, via an isomerase. All these isoforms are members of the retinoids, acting in different tissues after linkage with specific nuclear protein receptors. There are two families of RA receptors, the RARs (retinoic acid receptor α, β, and γ: RARA, RARB, RARG) and the RXRs (retinoid X receptor α, β and γ: RXRA, RXRB, RXRG). RARA (RARα) is involved essentially in hematopoiesis, while RARγ (RARG) is assigned to the skin. To be activated RARs can bind to ATRA or 9-cis-RA while RXRs bind only to 9-cis-RA (Allenby G et al., 1993).
Wild type RARA binds to DNA by its C domain, as a heterodimer with a related retinoid X receptor (RXR). The site of binding is a specific DNA sequence, the RA response element (RARE). The RARE domain is located in the promoter of target genes, it is composed classically of two direct repeats of a consensus sequence 5-PuG(G/T)CA-3, separated by 1, 2 or 5 base pairs named respectively DR1, DR2 and DR5 (Umesono K et al., 1991). In the absence of ligand the AF2 domain of the RARA protein associates with corepressors NCOR2 (also called SMRT: silencing mediator of retinoid thyroid hormones) and/or N-CoR (nuclear corepressor) which are members of a multiprotein repressor complex. In this complex SMRT and N-Cor associate with the Sin3 proteins (SIN3A and SIN3B) which then links to histone deacetylases HDAC1 and/or HDAC2. Histone deacetylation would produce a local structural modification of the chromatin with an arrest of transcription initiation (Beato M et al., 1995; Pazin MJ and Kadonaga JT, 1997; Melnick A and Licht JD, 1999).
Transport of the ligands ATRA and 9-cis-RA, and their link with RAR/RXR heterodimer are facilitated by another family of receptors, CRABP1 and CRABP2 (cellular retinoic acid binding proteins) (Bastie JN et al., 2001).
When the ligand reaches its target it binds to RARA on the AF2 domain and modifies the molecular conformation of the receptor, so that the repressor complex dissociates from the molecule and is replaced by coactivator proteins which can bind at the same site (Chambon P, 1996; Wade PA and Wolffe AP, 1997). These coactivators involve TRIM24 (also called TIF1), PSMC5 (also called TRIP1 or SUG1), NCOA2 (TIF2), NCOA3 (ACTR), NCOA1 (SRC-1), TAF4 (TAFII135), and CREBBP (CBP). PSMC5 has a DNA helicase activity, able to unwind DNA. CREBBP and NCOA3 have an histone acetylase activity, they bind to KAT2B (P/CAF) which is also an histone acetylase. Consequently, when RARA binds to its ligand ATRA, it becomes the member of a multiprotein complex, in association with RXR and a number of coactivators. The result is a local histone reacetylation leading to the modification of chromatin conformation and stimulation of transcription machinery.
The activity of many genes involved in myeloid maturation, including transcription factors, may be potentially triggered by this coactivators complex, resulting in the arrest of cell growth, terminal differentiation and production of mature granulocytes.

Homology

RARA shares homology with RARB and RARG, 9-cis RA receptors (RXRs) and receptors for thyroid and steroid hormones and for vitamine D3 ( VDR)

Implicated in

Top note

In oncogenesis, RARA has been primarily implicated in acute promyelocytic leukaemia (APL) induction, via the expression of the PML/RARA fusion gene. Apart from its fusion with PML, RARA gene may be seldom fused by translocation, with a great variety of genes (Chen Z et al., 1996; Redner RL, 2002; Adams J and Nassiri M, 2015; Yan W and Zhang G, 2016) and all these fusion genes contain the RARA C-terminal B through F domains, encoding DNA binding, retinoid X receptor (RXR) heterodimerization, ligand binding, and co-repressor and co-activator interaction functions of RARA, leading invariably and specifically to the development of an APL. In all the variant translocations the functional activity of PML is not altered showing the crucial role of RARA in the leukemogenesis process. On other part it was observed recently that RARB or RARG, instead of RARA, could exceptionally fuse with various genes, giving rise to an APL responding poorly to ATRA therapy (Osumi T et al., 2018; Miller CA et al.; 2018; Chen X et al., 2019)

Entity name

t(15;17)(q24;q21) / acute promyelocytic leukemia (APL) --> PML / RARA

Note

The translocation fuses the promyelocytic leukaemia gene (PML) at 15q24 with RARA (Kakizuka A et al., 1991; de Thé H et al., 1991).

Disease

Typical APL (or M3 AML, FAB classification), approximately 98% of APL cases; arrest of the white blood cells maturation at the promyelocytic stage giving an accumulation of abnormal promyelocytes with Auer rods and bundles (faggots); disruption of the PODs with a microspeckeled pattern; maturation response to all-trans retinoic acid (ATRA) therapy.

Prognosis

Immediate prognosis is impaired by intravascular disseminated coagulopathy; long term prognosis is favorable with treatment combining ATRA and/or arsenic trioxide (ATO) plus anthracycline chemotherapy (Wang Z-Y and Chen Z, 2008; Testa U and Lo-Coco F, 2016).
Treatment: More than 90% of complete remission with ATRA plus ATO. Additional gene(s) alterations, involving mainly FLT3, KRAS or CMYC, are considered as progression factors (de Thé H, 2018).

Cytogenetics

Variant or complex t(15;17) translocation in 5% of cases, no known prognosis implication; secondary chromosomal abnormalities in 30 to 35% of APL at diagnosis; association with +8 in 17 to 28% of cases; other associations are rare but recurrent: del(7q), del(9q), ider(17)t(15;17), +21. Rarely the t(15;17) is not detectable cytogenetically, resulting from a cryptic molecular insertion; if the insertion is too small, FISH analysis may be negative and the molecular analysis only will be able to detect the PML-RARA transcripts.

Hybrid gene

The crucial fusion transcript is 5PML-3RARA, encoded by der(15) chromosome; the counterpart 5RARA-3PML encoded by der(17) is inconstant.
The breakpoint in RARA gene is always located in intron between A and B domains.
PML gene is composed of approximately 53.000 bp with 9 exons; the PML protein is member of a multiprotein complex composing the matrix-associated nuclear bodies, which are dynamic nuclear components of 0.1 to 1.0 m in size. PML works as a tumour suppressor gene, the protein is implicated in a wide variety of cellular functions: apoptosis, differentiation, genome stability (Bernardi R and Pandolfi PP, 2007; Hsu K-S and Kao H-Y, 2018). There are three breakpoint clusters in PML gene: bcr1 (70% of patients), bcr2 (10%) and bcr3 (20%), giving rise respectively to the long (L), intermediate (V) and short (S) length hybrid PML-RARA transcripts; in the 3 types of proteins the coiled-coil domain of PML, which is an element of the ring-B box-CC/tripartite domain, is conserved; V form would be linked to ATRA with a decreased sensitivity and S form would be associated to an excess of secondary chromosome changes.

Fusion protein

106 Kda fusion protein; role in the leukemogenic process through two main pathways: 1) interference with the signalling pathway controlled by RARA and involved in differentiation and maturation of myeloid precursors (mainly dysregulation of retinoid-inducible genes responsible for in myeloid differentiation). 2) disruption of the PML nuclear bodies (PML-NBs) which control the P53 pathway and many other cellular functions involved in genome stability, apoptosis, cellular senescence, differentiation, angiogenesis.
In contrast with wild type RARA which only forms heterodimers with RXRA, the fusion protein PML/RARA can form homodimers through the coiled-coil domain of PML, which is the critical domain for the transformation of PML/RARA into an oncoprotein (Lin RJ and Evans RM, 2000; Occhionorelli M et al., 2011). The homodimer can link to the DNA, independently from RXR. The expression of PML/RARA homodimer is sufficient ex vivo to operate the cellular transformation, however the PML/RARA homodimer is quasi always linked in vivo to RXRA which is necessary to an efficient DNA binding. It results in a dominant negative control of both native PML and RARA functions (de Thé H et al., 1991; Melnick A and Licht JD, 1999; Occhionorelli M et al., 2011). Binding of the homodimer, by the RARA domain of PML-RARA, with DNA sites located in the promoter region of target genes, and multimerisation owing to the coiled-coil domain of PML, enhances the recruitment of co repressor proteins and of histone deacetylases (HDACs), leading to a gene repression via DNA methylation (Di Croce L et al., 2002; Martens JH et al., 2010; Occhionorelli M et al., 2011). The classical consequences are a block of myeloid differentiation at the promyelocytic stage. A second activity of PML-RARA is to disrupts the PML nuclear-bodies involved in many cellular regulations, particularly TP53 activation, leading to an increase of progenitors self renewal (Bernardi R and Pandolfi PP, 2007; Nasr R et al., 2008).

Molecular pathogenesis of APL.

Entity name

t(11;17)(q23;q12) / acute promyelocytic leukemia --> ZBTB16 / RARA

Note

Described in Chen Z et al., 1994; Licht JD et al., 1995; Melnick A and Licht JD, 1999; Sainty D et al., 2000. ZBTB16 is also named PLZF, ZNF145.

Disease

Variant acute promyelocytic leukemia (APL) form with atypical cytologic aspects: intermediate morphology between M2 and M3, less or not bilobed promyelocyte nucleus, no Auer rods, the hypogranular form is predominant with coarse granules, absence of faggot cells, increased number of hypogranular pseudo-Pelger neutrophils and increased CD56 expression; generally no response to ATRA therapy; however some cases achieved a remission with a treatment combining ATRA and chemotherapy or ATRA and G-CSF; worse prognostic than APL with t(15;17), whatever the treatment. Found in less than 1% of APL cases.

Cytogenetics

In some cases the translocation may be cryptic.

Hybrid gene

Native ZBTB16 (zinc finger and BTB domain containing 16) has 7 exons, 3 alternative transcripts; encodes a 673 amino acids zinc finger protein, containing one N-terminal POZ-BTB domain (Pox virus and Zinc finger domain also called Broad Complex, tramtrack, Bric a Brac ), one RD2 domain and 9 C-terminal zinc finger motifs. The native protein is involved as transcriptional repressor in a number of pathways during development (Liu et al., 2016). The t(11;17) results in two reciprocal transcripts, encoding in the same reading frame ZBTB16/RARA and RARA/ZBTB16 proteins. ZBTB16/RARA contains the same RARA domains as in PML/RARA.
Resistance to ATRA therapy is caused by the insensibility to ATRA of the corepressors-ZBTB16-/RARA complex, in which N-CoR/SMRT co repressor proteins maintain there link with the ZBTB16 part of ZBTB16/RARA, even with therapeutic levels of ATRA.

Entity name

t(5;17)(q35;q12) / acute promyelocytic leukemia --> NPM1 / RARA

Note

Described in Corey SJ et al., 1994; Redner RL et al., 1996; Rush EA et al., 2013. The translocation fuses the nucleophosmin gene (NPM1) with RARA. It is the second most frequent variant translocation after the t(11;17)(q23;q21). Apart from NPM1/RARA two other translocation / fusion gene involve NPM1 in haematological neoplasms: t(2;5)(p23;q35) NPM1/ALK fusion in anaplastic large cell lymphoma and t(3;5)(q25;q35) NPM1/MLF1 fusion in MDS and AML. Down or up regulation of NPM1 caused by mutations lead also to solid tumors (Grisendi S et al., 2006).

Disease

Exceptional; expresses overall similar morphologic and immunophenotypic features as classical APL; respond to ATRA treatment.

Hybrid gene

NPM1 encodes a nucleolar phosphoprotein mainly involved in ribosomal particles assembly and regulation of centrosome duplication. It is also implicated in the regulation of stability and activity of various tumor suppressor proteins, including TP53. It plays a crucial role in cell growth regulation and genomic stability. According to the physiological or physiopathological conditions NPM1 should be considered either as an oncoprotein or as a tumor suppressor (Grisendi S et al., 2006). The t(5;17) produces both NPM1/RARA and, inconstantly, RARA/NPM1 transcripts. Only NPM1/RARA protein is responsible for APL disease. As for PML/RARA and ZBTB16/RARA fusion genes the breakpoint in RARA occurs in the second intron so that its B-F domain is fused to the N-terminal domains of NPM1, in the same reading frame. The analysis of the initial published case (Redner RL et al., 1996) showed two different breakpoint in NPM1, generating two transcripts of 2.3 kb and 2.4 kb. Both coded two proteins of 520 and 563 amino acids respectively, with the same level of expression. These two fusion proteins had a RA-dependent transcriptional activity.

Entity name

t(11;17)(q13;q12) / acute promyelocytic leukemia --> NUMA1 / RARA

Note

Described in Wells RA et al., 1996, 1997, the third variant translocation to be described. Only one case reported to date, in a 6-month old male infant.

Disease

Presentation as a quite classical APL who expressed, however, multiple unexpected cutaneous lesions but peripheral blood smears and cellular immunophenotype were typical of APL. Respond to ATRA treatment and there was no relapse at 3 years after autologous bone marrow transplantation.

Hybrid gene

The NUMA1 gene (nuclear mitotic apparatus) located at 11q13, encodes NuMA, a high molecular weight (238 kDa) coiled-coil protein component of the nuclear matrix at interphase and associated with the spindle poles during mitosis. It is involved in the processes of mitosis and in the nuclear reconstructing after mitosis. NUMA1 is composed of a large coiled-col interstitial domain of approximately 1500 amino acids involved in homo-heterodimerization, encompassed with two globular C-terminal and N-terminal domains. The C-terminal domain contains a nuclear localization signal (NLS), a microtubule binding domain (MT), a LGN binding sequence and 4 phosphorylation sites. This complex domain is necessary for localization to the nucleus and mitotic spindle functioning. The N-terminal domain is required for post mitotic nuclear reassociation. Both N- and C-terminal domains contain DNA-binding S/TPXX motifs (Melnick A and Licht JD, 1999; Radulescu AE and Cleveland DW, 2010).
The t(11;17)(q13;q21) gave rise to a 2286 amino acids NUMA1/RARA fusion protein, linking in the same reading frame the B-F domain of RARA to the N-terminal globular and the coiled coil domains of NUMA1. No alternative RARA/ NUMA1 protein could be detected. NUMA1/RARA plays a role of dominant negative RA receptor. It is able to bind to quite the same RARE sites as PML/RARA, equally as a homodimer or a heterodimer with RXR but more stable as a RXR heterodimeric complex (Dong S et al., 2003).

Entity name

der(17) / acute promyelocytic leukemia --> STAT5B / RARA

Note

The STAT5B/RARA fusion gene is a rare event, no more than 12 cases were published in 2018. It results probably from a variable rearrangement of 17q, interstitial deletion, duplication, inversion or other more complex rearrangement, undetectable by conventional and molecular cytogenetic. However FISH with a commercial RARA dual colour or break apart probe is able sometimes to give informations, mainly in case of deletion of the 3-RARA sequences. In the first published case (Arnould C et al., 1999) der(17) resulted from a duplication of the 17q21.3-q23 segment.

Disease

Male predominance, only two female cases reported. Clinical and cytological data compatibles with variant APL or sometimes quite atypical for APL. Very poor response to ATRA and/or ATO therapy. No one long term complete remission could be obtained (Zang C et al., 2018).

Hybrid gene

The STAT5B gene (signal transducer and activator of transcription 5B) is located at 17q21.2, it contains 19 exons and a total of 5090 coding nucleotides. It is a member of the STAT family, it encodes a 92 kD S STAT5B protein which contains STAT proteins conserved domains: a N- terminal coiled coil domain, a DNA binding domain, a SH2 domain and a C-terminal transactivation domain. STAT5B is a signal transducer and activator of transcription, acting in the janus kinase (JAK)-STAT signaling pathway. It is activated by tyrosine-phosphorylation, permitting homo- or heteridimerization. Located inactive in the cytoplasm, the protein is rapidly translocated to the nucleus after dimerization and binds to DNA to activate its target genes (Del Rosario AM et al., 2012).
The STAT5B/RARA fusion protein is composed of the N- terminal coiled-coil domain necessary for dimerization, the DNA binding domain, the SH2 and a part of the SH3 domains of STAT5B, fused in the same reading frame to the B to F domains of RARA. No alterne RARA/ STAT5B protein is produced. Like PML/RARA, STAT5B /RARA binds to RARE as a homodimer or heterodimer with RXR. It works as a competitive inhibitor of transcriptional activity of RARA-RXR. This inhibition depends essentially on the presence of the coiled coil domain of STAT5B. When this domain is absent, in transfection experiments with modified STAT5B /RARA protein, STAT5B/RARA expresses the same transcriptional activity as wild type RARA (Dong S and Tweardy DJ, 2002; Huret JL, 2010).

Entity name

t(X;17) (p11;q21) / acute promyelocytic leukemia --> BCOR / RARA

Note

Described in Yamamoto Y et al., 2000. Only two cases reported to date, the first in a 45-year-old man with a 45,-Y, t(X;17)(p11;q21) karyotype.

Disease

First case clinical presentation as a variant APL, with 83% of promyelocytes in a hypercellular bone marrow and a coagulopathy, but with unusual rectangular and round cytoplasmic inclusion bodies in promyelocytes. Patient responded to ATRA therapy but was resistant to ATO.

Hybrid gene

The BCOR gene (BCL6 co repressor) located at Xp11.4 encodes a 180 kDa nuclear protein which is a component of a polycomb complex acting as a transcription suppressor. The BCOR/RARA fusion protein has a self association capacity through its BCOR-S region and ankyrin-repeat domain. It can also form a heterodimer with RXR to bind with RARE, acting as a dominant negative factor of RARA transcription.

Entity name

der(17) / acute promyelocytic leukemia --> PRKAR1A / RARA

Note

Described in Catalano A et al., 2007. Only one case published in a 66-year-old man. Karyotype showed only a trisomy 22. RARA break apart FISH showed a deletion of the 5-RARA probe on a der(17). A dual colour PML/RARA FISH showed a split of the RARA signal on der(17) and normal PML signals. Later on FISH with RARA and PRKAR1A probes confirmed the split of RARA and the PRKAR1A/RARA fusion on the der(17).

Disease

The patient was investigated for fatigue and anorexia. No signs of coagulopathy were observed, hypercellular bone marrow contained 83% of hypergranular promyelocytes, but without Auer rods or fagot cells. Patient responded well to ATRA and ATO.

Hybrid gene

PRKAR1A (protein kinase A regulatory subunit1) is located at 17q24.2. The protein is involved in the regulation of cAMP-dependent PRKA enzymatic activity. PRKAR1A/RARA binds to a number of RARE sequences, either as a homodimer or as a heterodimer with RXR. However, only the interaction of RXR with PRKAR1A/RARA is critical for leukemic transformation (Qiu JJ et al., 2010).

Entity name

t(4;17)(q12;q21) / acute promyelocytic leukemia --> FIP1L1 / RARA

Note

Described in Kondo T et al., 2008, Zamecnikova A, 2015. Seventh variant translocation to be described, three APL cases published, however the FIP1L1/RARA fusion was previously reported in one case of juvenile myelomonocytic leukaemia (Buijs A and Bruin M, 2007).

Disease

The first patient, a 90-year old woman, responded to ATRA therapy.

Hybrid gene

RARA breakpoint was, as expected, up side of exon 3 and it fused with exon 15 or exon 13 of FIP1 motif.

Entity name

der (2)t(2;17)(q32;q21) / acute promyelocytic leukemia --> NABP1 / RARA

Note

Described in Won D et al., 2013; Zamecnikova A, 2018.

Disease

Only one case described to date, a 59-year old man who achieved complete remission with ATRA followed by chemotherapy and allogenic bone marrow stem cells transplantation.

Hybrid gene

NABP1 (nucleic acid binding protein 1) also named OBFC2A (oligonucleotides / oligosaccharide binding fold containing 2A) is located at 2q32.3, it is involved in DNA damage response and genome stability. In the NABP1/RARA fusion gene exon 5 of the NABP1 gene is fused with the exon 3 of RARA.

Entity name

t(3;17)(26;q21) --> TBL1XR1 / RARA

Note

Described in Chen Y et al., 2014; Zamecnikova A, 2018.

Disease

Fusion gene detected in a patient with a complex translocation t(3;17)(q26;q21), t(7;17)(q11.2;q21). Three cases known to date. Response to ATRA therapy.

Hybrid gene

TBL1XR1/RARA (transducin beta-like 1 X-linked receptor 1) also known as TBLR1 (transducin beta-like protein 1-related protein). The TBL1XR1protein contains a LisH domain which is necessary for homo or heterodimerization, it could be involved in the TBL1XR1/RARA homodimerization.

Entity name

t(1;17)(q42;q21) --> IRF2BP2 /RARA

Note

Described in Yin CC et al., 2015 ; Shimomura Y et al., 2016 ; Jovanovic JV et al., 2017 ; Zamecnikova A, 2017 ; Mazharuddin S et al., 2018.

Disease

Four cases described in 2018, all with clinical, cytological and immunophenotypic features compatibles with APL. Two patients at least responded to ATRA therapy.

Hybrid gene

Breakpoint in IRF2BP2 (interferon regulatory factor 2 binding protein 2) exon 2 and in RARA intron 2.

Entity name

t(7;17)(q11;q21) --> GTF2I / RARA

Note

Described in Li J et al., 2015.

Disease

One case reported in a 35-year-old APL man which did not respond to ATRA therapy.

Hybrid gene

The t(7;17) unbalanced translocation resulted in a fusion between exon 6 of GTF2I and common exon 3 of RARA. GTF2I protein (general transcription factor 2I) is a members of the transcription factor 2I family. It contains a leucine zipper for homodimerization and a DNA binding domain. There are 4 human GTF2I isoforms which are expressed in various tissues.

Prognosis

In APL, resistance to ATRA was studied on GTF2I/RARA-transfected HL60 cells. It showed that the resistance was associated to the interaction between GTF2I/RARA and the RING finger protein 8 (RFN8) (Yan W et al., 2019).

Entity name

t(3;17)(q26;q21) --> FNDC3B / RARA

Note

Described in Cheng CK et al., 2017.

Disease

One case in a 36-year-old man. Cytology and immunophenotype were compatible with APL and patient responded to ATRA followed by chemotherapy and a complete remission was obtained at day 30, however patient relapsed at 8 months.

Hybrid gene

At the karyotypic level the translocation was the same as the t(3;17)(26;q21) which produce the TBLR1XR1/RARA fusion. DNA sequencing showed the FNDC3B/RARA fusion between exon 24 of FNDC3B and exon3 of RARA. Two reciprocal RARA-FNDC3B transcripts were detected. FNDC3B (fibronectin type III domain containing 3B) is implicated in protein interactions, particularly it has a role in granulocytic differentiation and it was involved in an APL-like leukaemia without RARA intervention (Wang HY et al., 2016)

Entity name

t(3;17)(q12;q21) --> TFG / RARA

Note

Described in Chong ML et al., 2018.

Disease

One case published in a 16-year-old man with a t(3;14;17) complex translocation. Bone marrow hypergranular promyelocytes and immunophenotype diagnosed an APL which responded to ATRA therapy.

Hybrid gene

RNA and cDNA sequencing showed a TFG/RARA fusion. TFG (TRK-fused gene) is located at 3q12.2, breakpoints of the fusion gene occurred in TFG exon 7 and RARA exon 3.

Entity name

Non APL malignancies

Disease

Mutations in the ligand binding domain of RARA, associated with MED12 gene mutations, were frequently observed in breast fibroadenoma and phyllode tumors (Tan J et al., 2015).
A super enhancer (SE) was observed at the RARA locus, in a subset of patients with AML other than APL. This SE was associated with a high RARA expression and evidences of differentiation in AML cell lines, leading to the hypothesis that non-APL AML patients with such a SE could be sensitive to RA therapy (McKeown MR et al.; 2017).
t(11;17)(q23;q12) / M5 acute myeloid leukemia --> KMT2A / RARA 1 case to date (Shekhter-Levin et al.2000); not found in APL; belongs to the MLL/11q23 leukemias

Breakpoints

Article Bibliography

Pubmed ID	Last Year	Title	Authors
26414475	2015	Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations.	Adams J et al
8380496	1993	Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids.	Allenby G et al
10441338	1999	The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia.	Arnould C et al
11682061	2001	The novel co-activator CRABPII binds to RARalpha and RXRalpha via two nuclear receptor interacting domains and does not require the AF-2 'core'.	Bastie JN et al
8521509	1995	Steroid hormone receptors: many actors in search of a plot.	Beato M et al
17928811	2007	Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies.	Bernardi R et al
17301809	2007	Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia.	Buijs A et al
17712046	2007	The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia.	Catalano A et al
22480366	2012	Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders.	Celestino-Soper PB et al
8801176	1996	A decade of molecular biology of retinoic acid receptors.	Chambon P et al
29736267	2018	Long non-coding RNAs: crucial regulators of gastrointestinal cancer cell proliferation.	Chen J et al
30996344	2019	A novel NPM1-RARG-NPM1 chimeric fusion in acute myeloid leukaemia resembling acute promyelocytic leukaemia but resistant to all-trans retinoic acid and arsenic trioxide.	Chen X et al
24782508	2014	TBLR1 fuses to retinoid acid receptor α in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia.	Chen Y et al
8302850	1994	PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors.	Chen Z et al
8721678	1996	Retinoic acid regulatory pathways, chromosomal translocations, and acute promyelocytic leukemia.	Chen Z et al
28314734	2017	FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia.	Cheng CK et al
14519448	2003	Direct and biochemical interaction between dopamine D3 receptor and elongation factor-1Bbetagamma.	Cho DI et al
26472928	2015	Assembly of Multi-tRNA Synthetase Complex via Heterotetrameric Glutathione Transferase-homology Domains.	Cho HY et al
30292835	2018	TFG-RARA: A novel fusion gene in acute promyelocytic leukemia that is responsive to all-trans retinoic acid.	Chong ML et al
8057672	1994	A non-classical translocation involving 17q12 (retinoic acid receptor alpha) in acute promyelocytic leukemia (APML) with atypical features.	Corey SJ et al
11834837	2002	Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor.	Di Croce L et al
12584566	2003	Essential role for the dimerization domain of NuMA-RARalpha in its oncogenic activities and localization to NuMA sites within the nucleus.	Dong S et al
11929748	2002	Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways.	Dong S et al
22685290	2012	Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18.	Du Y et al
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Other Information

Locus ID:

NCBI: 5914
MIM: 180240
HGNC: 9864
Ensembl: ENSG00000131759

Variants:

dbSNP: 5914
ClinVar: 5914
TCGA: ENSG00000131759
COSMIC: RARA

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000131759	ENST00000254066	P10276
ENSG00000131759	ENST00000254066	Q6I9R7
ENSG00000131759	ENST00000394081	P10276
ENSG00000131759	ENST00000394081	F1D8N9
ENSG00000131759	ENST00000394086	A8MUP8
ENSG00000131759	ENST00000394089	P10276
ENSG00000131759	ENST00000394089	Q6I9R7
ENSG00000131759	ENST00000425707	P10276
ENSG00000131759	ENST00000475125	J3KSJ4
ENSG00000131759	ENST00000577646	J3QRM2

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Acute myeloid leukemia	KEGG	ko05221
Pathways in cancer	KEGG	hsa05200
Acute myeloid leukemia	KEGG	hsa05221
Transcriptional misregulation in cancer	KEGG	ko05202
Transcriptional misregulation in cancer	KEGG	hsa05202
Signal Transduction	REACTOME	R-HSA-162582
Signaling by Retinoic Acid	REACTOME	R-HSA-5362517
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Nuclear Receptor transcription pathway	REACTOME	R-HSA-383280
Developmental Biology	REACTOME	R-HSA-1266738
Activation of HOX genes during differentiation	REACTOME	R-HSA-5619507
Activation of anterior HOX genes in hindbrain development during early embryogenesis	REACTOME	R-HSA-5617472
Th17 cell differentiation	KEGG	ko04659
Th17 cell differentiation	KEGG	hsa04659

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA448486	arsenic trioxide	Chemical	LabelAnnotation	associated
PA451746	tretinoin	Chemical	LabelAnnotation	associated

References

Pubmed ID	Year	Title	Citations
38418133	2024	Clinical Relevance of Differential RARα and PPARβ/δ Expression in Myelodysplastic Syndromes.	0
38648485	2024	PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells.	1
38418133	2024	Clinical Relevance of Differential RARα and PPARβ/δ Expression in Myelodysplastic Syndromes.	0
38648485	2024	PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells.	1
36216898	2023	Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα.	0
36759620	2023	Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia.	3
36216898	2023	Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα.	0
36759620	2023	Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia.	3
35622143	2022	PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As(2)O(3) by stabilizing oncoprotein PML-RARα.	2
35622143	2022	PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As(2)O(3) by stabilizing oncoprotein PML-RARα.	2
32735792	2021	No prognostic significance of normalized copy number of PML-RARA transcript at diagnosis in patients with acute promyelocytic leukemia.	1
32854112	2021	A PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia.	31
33647291	2021	Structural Insights into the Interaction of the Intrinsically Disordered Co-activator TIF2 with Retinoic Acid Receptor Heterodimer (RXR/RAR).	7
33935126	2021	Impact of RARα and miR-138 on retinoblastoma etoposide resistance.	2
34042280	2021	Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia.	9

Citation

Franck Vigué

RARA (Retinoic acid receptor, alpha)

Atlas Genet Cytogenet Oncol Haematol. 2020-03-01

Online version: http://atlasgeneticsoncology.org/gene/46/css/lib/gene-fusions/hgnc

Historical Card

2000-10-01 RARA (Retinoic acid receptor, alpha) by Franck Vigué Affiliation

franck.viguie@free.fr