Gene Summary

Gene:RARA; retinoic acid receptor alpha
Aliases: RAR, NR1B1
Summary:This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.[provided by RefSeq, Sep 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:retinoic acid receptor alpha
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (61)
Pathways:What pathways are this gene/protein implicaed in?
Show (6)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • p21-Activated Kinases
  • Chromosome 15
  • Homologous Transplantat
  • Childhood Cancer
  • Nuclear Proteins
  • Cell Differentiation
  • Signal Processing, Computer-Assisted
  • Cell Proliferation
  • Receptors, Retinoic Acid
  • Neoplastic Cell Transformation
  • Single Nucleotide Polymorphism
  • Telomere
  • Leukaemia
  • Cancer Types
  • Leukemia, Promyelocytic, Acute
  • Antineoplastic Agents
  • Retinoic Acid
  • Messenger RNA
  • Chromosome Aberrations
  • Arsenicals
  • Gene Expression Profiling
  • Leukemic Gene Expression Regulation
  • Arsenic Trioxide
  • Remission, Spontaneous
  • Adolescents
  • Karyotyping
  • Transcription Factors
  • mRNA Cleavage and Polyadenylation Factors
  • WT1
  • NPM1
  • Drug Resistance
  • Biomarkers, Tumor
  • RARA
  • PML
  • Chromosome 17
  • Zinc Fingers
  • Breast Cancer
  • Promyelocytic Leukemia Protein
  • FISH
  • RARA
  • Cancer Gene Expression Regulation
  • Receptors, Cytoplasmic and Nuclear
  • Oxides
  • Acute Myeloid Leukaemia
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Childhood CancersRARA and Childhood Acute Promyelocytic Leukaemia View Publications69
Leukaemiat(5;17)(q32;q11) RARA-NPM translocations in Acute Promyelocytic Leukemia
Acute Myeloid Leukaemia (AML)t(11;17)(q32;q21) RARA-PLZF in Acute Promyelocytic Leukemia
Leukaemiat(15;17)(q21;q21) RARA-PML translocation in Acute Promyelocytic Leukaemia

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RARA (cancer-related)

Ishigami-Yuasa M, Ekimoto H, Kagechika H
Class IIb HDAC Inhibition Enhances the Inhibitory Effect of Am80, a Synthetic Retinoid, in Prostate Cancer.
Biol Pharm Bull. 2019; 42(3):448-452 [PubMed] Related Publications
Combination therapy is often an effective strategy to treat cancer. In this study, we examined the growth-inhibitory effects of Am80 (tamibarotene), a specific retinoic acid receptor (RAR) α/β agonist, in combination with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), or a DNA methyl transferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine, on androgen receptor (AR)-positive and AR-negative prostate cancer cell lines (LNCaP and PC-3, respectively). We found that the combination therapy of SAHA and Am80 showed an enhanced growth-inhibitory effect on LNCaP cells. Further studies with various HDAC isotype-selective inhibitors showed that SAHA and KD5170 (a selective class I and II HDAC inhibitor) each increased the RARα protein level in LNCaP cells. Our results indicate that the target of the enhancing effect belongs to the Class IIb HDACs, especially HDAC6. Dual targeting of Class IIb HDAC and RARα may be a candidate therapeutic strategy for prostate cancer.

Yuan D, Cui M, Yu S, et al.
Droplet digital PCR for quantification of PML-RARα in acute promyelocytic leukemia: a comprehensive comparison with real-time PCR.
Anal Bioanal Chem. 2019; 411(4):895-903 [PubMed] Related Publications
Real-time quantitative PCR (qPCR) has been widely implemented for molecular testing, but there are still some inherent limitations that hamper its usefulness. Droplet digital PCR (ddPCR), which can provide direct, standards-free quantification, has recently received increasing attention. In our study, a comprehensive comparison of ddPCR with qPCR in relation to the quantification of PML-RARα was performed to evaluate the diagnostic potential of ddPCR. Results showed that ddPCR displayed significant concordance with qPCR in the detection of PML-RARα in clinical samples, but showed advantages over qPCR in terms of precision, limit of detection (LOD), and other basic performance parameters. A study of the feasibility of duplexing also indicated that ddPCR could simultaneously quantify the target PML-RARα and the clinical common reference gene ABL in a reaction, in contrast to qPCR. Moreover, ddPCR was more tolerant than qPCR of inhibition, and was shown to be able to quantify inhibition-prone samples. Another advantage of using ddPCR in clinical applications is that it will yield accurate results for patients with PML-RARα levels that fluctuate around the LOD of qPCR. Therefore, ddPCR is considered to have the potential to become a reliable alternative technique for quantifying PML-RARα. Graphical abstract ᅟ.

Luo Q, Deng W, Wang H, et al.
BRD4 interacts with PML/RARα in acute promyelocytic leukemia.
Front Med. 2018; 12(6):726-734 [PubMed] Related Publications
Bromodomain-containing 4 (BRD4) has been considered as an important requirement for disease maintenance and an attractive therapeutic target for cancer therapy. This protein can be targeted by JQ1, a selective small-molecule inhibitor. However, few studies have investigated whether BRD4 influenced acute promyelocytic leukemia (APL), and whether BRD4 had interaction with promyelocytic leukemia-retinoic acid receptor α (PML/RARα) fusion protein to some extent. Results from cell viability assay, cell cycle analysis, and Annexin-V/PI analysis indicated that JQ1 inhibited the growth of NB4 cells, an APL-derived cell line, and induced NB4 cell cycle arrest at G1 and apoptosis. Then, we used co-immunoprecipitation (co-IP) assay and immunoblot to demonstrate the endogenous interaction of BRD4 and PML/RARα in NB4 cells. Moreover, downregulation of PML/RARα at the mRNA and protein levels was observed upon JQ1 treatment. Furthermore, results from the RT-qPCR, ChIP-qPCR, and re-ChIP-qPCR assays showed that BRD4 and PML/RARα co-existed on the same regulatory regions of their target genes. Hence, we showed a new discovery of the interaction of BRD4 and PML/RARα, as well as the decline of PML/RARα expression, under JQ1 treatment.

Iaccarino L, Divona M, Ottone T, et al.
Identification and monitoring of atypical PML/RARA fusion transcripts in acute promyelocytic leukemia.
Genes Chromosomes Cancer. 2019; 58(1):60-65 [PubMed] Related Publications
Once the diagnostic suspicion of acute promyelocytic leukemia (APL) has been raised, international guidelines recommend prompt initiation of tailored therapy and supportive care, while awaiting for genetic confirmation of the diagnosis, and the identification of the specific PML/RARA isoform by reverse transcriptase polymerase chain reaction (RT-PCR). Depending on the PML break point, usually located within intron 6, exon 6, or intron 3, different PML/RARA transcript isoforms may be generated, that is, long (bcr1), variant (bcr2), and short (bcr3), respectively. We report here the characterization of three APL cases harboring atypical PML/RARA transcripts, which were not clearly detectable after standard RT-PCR amplification. In all three cases, clinical, morphological, and immunophenotypic features were consistent with APL. Direct sequencing allowed the identification of atypical break points within the PML and RARA genes. Then, we designed a patient-specific quantitative real-time PCR for the atypical transcripts, which allowed for specific quantitative evaluation of minimal residual disease (MRD) during follow-up. Despite the rarity of APL cases with an atypical PML/RARA fusion, our study indicates that an integrated laboratory approach, employing several diagnostic techniques is crucial to timely diagnose APL. This approach allows prompt initiation of specific targeted treatment and reliable MRD monitoring in atypical APL cases.

Hattori H, Ishikawa Y, Kawashima N, et al.
Identification of the novel deletion-type PML-RARA mutation associated with the retinoic acid resistance in acute promyelocytic leukemia.
PLoS One. 2018; 13(10):e0204850 [PubMed] Free Access to Full Article Related Publications
All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are essential for acute promyelocytic leukemia (APL) treatment. It has been reported that mutations in PML-RARA confer resistance to ATRA and ATO, and are associated with poor prognosis. Although most PML-RARA mutations were point mutations, we identified a novel seven amino acid deletion mutation (p.K227_T233del) in the RARA region of PML-RARA in a refractory APL patient. Here, we analyzed the evolution of the mutated clone and demonstrated the resistance of the mutated clone to retinoic acid (RA). Mutation analysis of PML-RARA was performed using samples from a chemotherapy- and ATRA-resistant APL patient, and the frequencies of mutated PML-RARA transcript were analyzed by targeted deep sequencing. To clarify the biological significance of the identified PML-RARA mutations, we analyzed the ATRA-induced differentiation and PML nuclear body formation in mutant PML-RARA-transduced HL-60 cells. At molecular relapse, the p.K227_T233del deletion and the p.R217S point-mutation in the RARA region of PML-RARA were identified, and their frequencies increased after re-induction therapy with another type of retinoiec acid (RA), tamibarotene. In deletion PML-RARA-transduced cells, the CD11b expression levels and NBT reducing ability were significantly decreased compared with control cells and the formation of PML nuclear bodies was rarely observed after RA treatment. These results indicate that this deletion mutation was closely associated with the disease progression during RA treatment.

Tsuchiya K, Tabe Y, Ai T, et al.
Eprobe mediated RT-qPCR for the detection of leukemia-associated fusion genes.
PLoS One. 2018; 13(10):e0202429 [PubMed] Free Access to Full Article Related Publications
The detection and quantification of leukemia-associated fusion gene transcripts play important roles in the diagnosis and follow-up of leukemias. To establish a standardized method without interlaboratory discrepancies, we developed a novel one-step reverse transcription quantitative PCR (RT-qPCR) assay, called "the Eprobe leukemia assay," for major and minor BCR-ABL1, RUNX1-RUNX1T1, and various isoforms of PML-RARA. This assay is comprised of Eprobes that are exciton-controlled hybridization-sensitive fluorescent oligonucleotides. Melting curve analyses were performed on synthetic quantitative standard RNAs with strict quality control. Quantification capacity was evaluated by comparison with TaqMan RT-qPCR using 67 primary leukemia patient samples. The lower limit of detection and the limit of quantification of this assay were less than 31.3 copies/reaction and 62.5 copies/reaction, respectively. This assay correctly detected the fusion genes in samples with 100% sensitivity and specificity. The specificity of the reactions was confirmed by melting curve analyses. The assay detected low-level expression of minor BCR-ABL1 co-expressed with major BCR-ABL1. These results illustrate the feasibility and high accuracy of the Eprobe leukemia assay, even for minimal residual disease monitoring.

Gaillard C, Surianarayanan S, Bentley T, et al.
Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia.
Blood Adv. 2018; 2(19):2462-2466 [PubMed] Free Access to Full Article Related Publications
Although the role of promyelocytic leukemia/retinoic acid receptor α (PML/RARA) fusion protein is well recognized in acute promyelocytic leukemia (APL), its contribution to initiation and maintenance of leukemogenesis is not completely understood. Transcriptome analysis in the murine

Jian Z, Cheng T, Zhang Z, et al.
Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma.
Cell Mol Gastroenterol Hepatol. 2018; 6(4):429-449 [PubMed] Free Access to Full Article Related Publications
Background & Aims: Although nearly half of pancreatic ductal adenocarcinoma (PDAC) patients have diabetes mellitus with episodes of hyperglycemia, its tumor microenvironment is hypoglycemic. Thus, it is crucial for PDAC cells to develop adaptive mechanisms dealing with oscillating glucose levels. So far, the biological impact of such glycemic variability on PDAC biology remains unknown.
Methods: Murine PDAC cells were cultured in low- and high-glucose medium to investigate the molecular, biochemical, and metabolic influence of glycemic variability on tumor behavior. A set of in vivo functional assays including orthotopic implantation and portal and tail vein injection were used. Results were further confirmed on tissues from PDAC patients.
Results: Glycemic variability has no significant effect on PDAC cell proliferation. Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization. Increased metastatic colonization under hyperglycemia is due to increased expression of runt related transcription factor 3 (Runx3), which further activates expression of collagen, type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic pathway. Through epigenetic machinery, retinoic acid receptor beta (Rarb) expression fluctuates according to glycemic variability, acting as a critical sensor relaying the glycemic signal to Runx3/Col6a1. Moreover, the signal axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to a widely used antidiabetic substance, metformin, and Rar modulator. Finally, PDAC tissues from patients with diabetes show an increased expression of COL6A1.
Conclusions: Glycemic variability promotes both local invasion and metastatic colonization of PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose activity is controlled by glycemic variability is identified. The therapeutic relevance of this pathway needs to be explored in PDAC patients, especially in those with diabetes.

Mao XM, Li H, Zhang XY, et al.
Retinoic Acid Receptor α Knockdown Suppresses the Tumorigenicity of Esophageal Carcinoma via Wnt/β-catenin Pathway.
Dig Dis Sci. 2018; 63(12):3348-3358 [PubMed] Related Publications
BACKGROUND: Aberrant expression of retinoic acid receptor α (RARα) was correlated with diverse carcinomas such as acute promyelocytic leukemia and colorectal carcinoma. Nevertheless, the function and mechanism of RARα in esophageal carcinoma (EC) remain unclear.
AIM: To investigate the expression of RARα in EC and its effect in the tumorigenesis of EC.
METHODS AND RESULTS: In immunohistochemistry study, RARα was overexpressed in human EC tissues, and its overexpression was closely related to the pathological differentiation, lymph node metastasis, and clinical stages in EC patients. Functionally, RARα knockdown suppressed the proliferation and metastasis of EC cells through downregulating the expression of PCNA, Ki67, MMP7, and MMP9, as well as enhanced drug susceptibility of EC cells to 5-fluorouracil and cisplatin. Mechanistically, RARα knockdown inhibited the activity of Wnt/β-catenin pathway through reducing the phosphorylation level of GSK3β at Ser-9 and inducing phosphorylation level at Tyr-216, which resulted in downregulation of its downstream targets such as MMP7, MMP9, and P-gP.
CONCLUSIONS: Our results demonstrated that RARα knockdown suppressed the tumorigenicity of EC via Wnt/β-catenin pathway. RARα might be a potential molecular target for EC clinical therapy.

Wang S, Chai P, Jia R, Jia R
Novel insights on m
Mol Cancer. 2018; 17(1):101 [PubMed] Free Access to Full Article Related Publications
N6-methyladenosine (m

Cicconi L, Fenaux P, Kantarjian H, et al.
Molecular remission as a therapeutic objective in acute promyelocytic leukemia.
Leukemia. 2018; 32(8):1671-1678 [PubMed] Related Publications
Acute promyelocytic leukemia (APL) is a subtype of acute leukemia characterized by a unique t(15;17) translocation generating the PML/RARA fusion gene and hybrid oncoprotein. Besides its critical role in leukemogenesis, this genetic aberration serves as a disease-specific biomarker for rapid diagnosis and monitoring of minimal residual disease (MRD). Moreover, PML/RARA is specifically targeted by All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two agents that synergistically act to induce degradation of the oncoprotein. Large clinical studies including two randomized trials conducted in newly diagnosed APL patients have shown that the ATRA-ATO combination is superior to conventional ATRA and chemotherapy both in terms of efficacy and safety. Preliminary studies using oral formulations of arsenic and ATRA suggest that oral arsenic is as effective and manageable as intravenous ATO. Following early retrospective studies indicating the prognostic relevance of PML/RARA monitoring, several prospective studies were conducted in large cohorts of APL patients enrolled in clinical trials with the aim of better assessing the prognostic value of longitudinal PCR testing. The results consistently showed that molecular remission (defined as negativization of the PCR test for PML/RARA) correlates with a significantly decreased risk of relapse, whereas persistence of PCR positivity for PML/RARA after consolidation or conversion from negative to positive during follow-up is strongly associated with hematologic relapse. Based on these data, various groups started using pre-emptive salvage therapy for patients who persisted PCR-positive after frontline consolidation or converted from negative to positive PCR during follow-up. Finally, several expert panels have recommended that molecular remission should be considered a therapeutic objective in APL, and molecular response has been adopted as a study endpoint in modern clinical trials.

Einbond LS, Soffritti M, Esposti DD, et al.
A transcriptomic analysis of black cohosh: Actein alters cholesterol biosynthesis pathways and synergizes with simvastatin.
Food Chem Toxicol. 2018; 120:356-366 [PubMed] Related Publications
Previous studies indicate that the herb black cohosh (Actaea racemosa L.) and the triterpene glycoside actein inhibit the growth of human breast cancer cells and activate stress-associated responses. This study assessed the transcriptomic effects of black cohosh and actein on rat liver tissue, using Ingenuity and ToxFX analyses. Sprague-Dawley rats were treated with an extract of black cohosh enriched in triterpene glycosides (27%) for 24 h or actein for 6 and 24 h, at 35.7 mg/kg, and liver tissue collected for gene expression analysis. Ingenuity analysis indicates the top canonical pathways are, for black cohosh, RAR Activation, and, for actein, Superpathway of Cholesterol Biosynthesis, at 24 h. Actein alters the expression of cholesterol biosynthetic genes, but does not inhibit HMG-CoA reductase activity. Black cohosh and actein inhibited the growth of human breast and colon cancer cells and synergized with the statin simvastatin. Combinations of black cohosh with certain classes of statins could enhance their activity, as well as toxic, such as inflammatory liver, side effects. Transcriptomic analysis indicates black cohosh and actein warrant further study to prevent and treat cancer and lipid disorders. This study lays the basis for an approach to characterize the mode of action and toxicity of herbal medicines.

Marchwicka A, Marcinkowska E
Regulation of Expression of CEBP Genes by Variably Expressed Vitamin D Receptor and Retinoic Acid Receptor α in Human Acute Myeloid Leukemia Cell Lines.
Int J Mol Sci. 2018; 19(7) [PubMed] Free Access to Full Article Related Publications
All-trans-retinoic acid (ATRA) and 1α,25-dihydroxyvitamin D (1,25D) are potent inducers of differentiation of myeloid leukemia cells. During myeloid differentiation specific transcription factors are expressed at crucial developmental stages. However, precise mechanism controlling the diversification of myeloid progenitors is largely unknown, CCAAT/enhancer-binding protein (C/EBP) transcription factors have been characterized as key regulators of the development and function of the myeloid system. Past data point at functional redundancy among C/EBP family members during myeloid differentiation. In this study, we show that in acute myeloid leukemia (AML) cells, high expression of vitamin D receptor gene (

Zare S, Lin L, Alghamdi AG, et al.
Comparative Pathologic Analysis of Breast Cancers Classified as HER2/neu-Amplified by FISH Using a Standard HER2/CEP17 Dual Probe and an Alternative Chromosome 17 Control Probe.
Am J Surg Pathol. 2018; 42(9):1208-1215 [PubMed] Related Publications
At our institution, breast cancer cases that generate an equivocal HER2/neu (HER2) result by fluorescence in situ hybridization (FISH) using the dual HER2/chromosome enumeration probe (CEP17) are reflexed to an assay that utilizes an alternative control probe (lissencephaly gene1 [LIS1] [17p13.3]/retinoic acid receptor α [RARA] [17q21.2]). This study examines whether cancers that are classified as HER2-amplified with an alternate probe are clinicopathologically similar to those that are classified as such using the HER2/CEP17 probe. Reports for 1201 breast cancers were reviewed, and clinicopathologic findings were compared between HER2/CEP17-equivocal cases that became HER2-amplified using the alternate probe (group A: n=48), HER2-amplified cases using the HER2/CEP17 probe (group B: n=169), and HER2-nonamplified cases using the HER2/CEP17 probe (group C: n=910). Of 1201 cases tested using the HER2/CEP17 probe, 169 (14%) were HER2-amplified, 122 (10%) were equivocal, and 910 (76%) were nonamplified. Additional testing with the alternative probe on the 122 equivocal cases reclassified 48 (39%) of them to HER2-amplified, and such cases comprised 22% of all HER2-amplified tumors. A higher proportion of tumors with HER2 copy number between 5.0 and 5.9 became positive upon additional testing when compared with those with a priori HER2 copy numbers between 4.0 and 4.9 (P=0.0362). Group A cases, compared with group B cases, were more frequently positive for estrogen receptor (97.91% vs. 72.18%, P<0.0001) and progesterone receptor (85.41% vs. 59.17%, P=0.0009). Most group A cases (71%) were HER2 equivocal (score 2+) by immunohistochemistry, whereas most group B cases (60%) were positive (score 3+). Groups A and B showed no significant differences regarding patient age, lymph node status, tumor grade, histotype, and stage distribution. In summary, among our HER2-amplified cohort of breast cancers, alternative probe-detected cases were more frequently estrogen receptor and progesterone receptor positive than HER2/CEP17-detected cases, and were more frequently discordant with HER2 immunohistochemistry results. These findings raise the possibility of underlying biologic differences between these 2 groups, which warrants further study. However, the tumors were largely comparable regarding all other clinicopathologic variables. As it is unknown whether HER2-targeted therapy is truly beneficial in this subgroup of patients, future clinical trials should specifically evaluate this subset.

Suguna E, Farhana R, Kanimozhi E, et al.
Acute Myeloid Leukemia: Diagnosis and Management Based on Current Molecular Genetics Approach.
Cardiovasc Hematol Disord Drug Targets. 2018; 18(3):199-207 [PubMed] Related Publications
BACKGROUND & OBJECTIVE: Acute Myeloid Leukemia (AML) is characterized by the accumulation of ≥20% myeloid premature blast cells in the bone marrow and they are most often found in the peripheral blood. AML is generally classified based on either French-American-British (FAB) or World Health Organization (WHO) systems. For better clinical management, cytogenetic finding in AML is necessary and in patients with normal karyotypes - molecular, epigenetic and proteomic biomarkers are very important in choosing which drugs to prescribe. Mutations of certain genes like NPM1, FLT3, CEBPA, RUNX1 and MLL play a crucial role in the risk management and clinical stratification of AML patients. We reviewed the literature for the current trends of clinical practice based on laboratory based diagnostic tests in AML. Outcome and Result: We listed in AML chromosomal aberrations (translocations, fusions or RUNX1, CBFB, MYHI1, MLL, EVI1, PML-RARA), genes and mutations (NPM1, FLT3, CEPBA, MLL) epigenetic factors (DNMT34, TET2) and proteomic biomarkers (PTP, PTK, PIP) and analysed how on the basis of these factors medical risk was stratified and accordingly managed.
CONCLUSION: AML is genetically and functionally a heterogenous malignant disease. In the western world, leukemia is one of the most common among all cancers. India is ranked 3rd in cancer disease after United States of America and China. Cytogenetic analysis, molecular/proteomic biomarkers and epigenetic factors assist in determining the management strategies and prognosis of the disease. A number of targeted drugs in pre-clinical and clinical trials based on molecular factors and epigenetic mechanisms have been reported to have promising results in AML patients.

Tsuchiya H, Oura S
Involvement of MAFB and MAFF in Retinoid-Mediated Suppression of Hepatocellular Carcinoma Invasion.
Int J Mol Sci. 2018; 19(5) [PubMed] Free Access to Full Article Related Publications
Retinoids exert antitumor effects through the retinoic acid receptor α (RARα). In the present study, we sought to identify the factors involved in the RARα-mediated transcriptional regulation of the tumor suppressor gene and the tissue factor pathway inhibitor 2 (TFPI2) in hepatocellular carcinoma (HCC). All-

Song C, Wang L, Wu X, et al.
PML Recruits TET2 to Regulate DNA Modification and Cell Proliferation in Response to Chemotherapeutic Agent.
Cancer Res. 2018; 78(10):2475-2489 [PubMed] Free Access to Full Article Related Publications
Aberrant DNA methylation plays a critical role in the development and progression of cancer. Failure to demethylate and to consequently reactivate methylation-silenced genes in cancer contributes to chemotherapeutic resistance, yet the regulatory mechanisms of DNA demethylation in response to chemotherapeutic agents remain unclear. Here, we show that promyelocytic leukemia (PML) recruits ten-eleven translocation dioxygenase 2 (TET2) to regulate DNA modification and cell proliferation in response to chemotherapeutic agents. TET2 was required by multiple chemotherapeutic agents (such as doxorubicin) to prmote 5-hydroxymethylcytosine (5hmC) formation. Stable isotope labeling with amino acids in cell culture, followed by immunoprecipitation-mass spectrometry, identified potential binding partners of TET2, of which PML mostly enhanced 5hmC formation. PML physically bound to TET2 via the PML C-terminal domain and recruited TET2 to PML-positive nuclear bodies. This interaction was disrupted by the PML-RARA t(15;17) mutation, which stems from chromosomal translocation between DNA encoding the C-terminal domain of PML and the retinoic acid receptor alpha (RARA) gene. In response to chemotherapeutic drugs, PML recruited TET2, regulated DNA modification, reactivated methylation-silenced genes, and impaired cell proliferation. Knockout of PML abolished doxorubicin-promoted DNA modification. In addition, PML and TET2 levels positively correlated with improved overall survival in patients with head and neck cancer. These findings shed insight into the regulatory mechanisms of DNA modification in response to chemotherapeutic agents.

Wang L, Sun Y, Sun Y, et al.
First case of AML with rare chromosome translocations: a case report of twins.
BMC Cancer. 2018; 18(1):458 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Leukemia is different from solid tumor by harboring genetic rearrangements that predict prognosis and guide treatment strategy. PML-RARA, RUNX1-RUNX1T1, and KMT2A-rearrangement are common genetic rearrangements that drive the development of acute myeloid leukemia (AML). By contrast, rare genetic rearrangements may also contribute to leukemogenesis but are less summarized.
CASE PRESENTATION: Here we reported rare fusion genes ZNF717-ZNF37A, ZNF273-DGKA, and ZDHHC2-TTTY15 in a 47-year-old AML-M4 patient with FLT3 internal tandem duplication (ITD) discovered by whole genome sequencing (WGS) using the patient's healthy sibling as a sequencing control.
CONCLUSION: This is, to our knowledge, the first case of AML with fusion gene ZNF717-ZNF37A, ZNF273-DGKA, and ZDHHC2-TTTY15.

Chen J, Cao X, An Q, et al.
Inhibition of cancer stem cell like cells by a synthetic retinoid.
Nat Commun. 2018; 9(1):1406 [PubMed] Free Access to Full Article Related Publications
Developing novel drugs that can abrogate the growth and metastasis of malignant tumors is a major challenge for cancer researchers. Here we describe a novel synthetic retinoid, namely WYC-209, which inhibits proliferation of malignant murine melanoma tumor-repopulating cells (TRCs), known to resist conventional drug treatment, with an IC

Li YT, Tian XT, Wu ML, et al.
Resveratrol Suppresses the Growth and Enhances Retinoic Acid Sensitivity of Anaplastic Thyroid Cancer Cells.
Int J Mol Sci. 2018; 19(4) [PubMed] Free Access to Full Article Related Publications
Anaplastic thyroid cancer (ATC) is a highly lethal undifferentiated malignancy without reliable therapies. Retinoic acid (RA) has been employed to promote redifferentiation of thyroid cancers by increasing their I

Agersborg S, Mixon C, Nguyen T, et al.
Immunohistochemistry and alternative FISH testing in breast cancer with HER2 equivocal amplification.
Breast Cancer Res Treat. 2018; 170(2):321-328 [PubMed] Free Access to Full Article Related Publications
PURPOSE: While HER2 testing is well established in directing appropriate treatment for breast cancer, a small percentage of cases show equivocal results by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Alternative probes may be used in equivocal cases. We present a single community-based institution's experience in further evaluating these cases.
PATIENTS AND METHODS: Between 2014 and 2016, 4255 samples were submitted for HER2 amplification testing by alternative probes, TP53, RAI1, and RARA. Of the patients tested by FISH, 505/3908 (12.9%) also had IHC data.
RESULTS: Most (73.9%) FISH equivocal cases remained equivocal after IHC testing. However, 50.5% of equivocal cases were classified as HER2 amplified by alternative probes. Most cases were positive by more than one probe: 78% of positive cases by RAI1 and 73.9% by TP53. There was a significant difference between IHC and FISH alternative testing (p < 0.0001) among the equivocal cases by conventional FISH testing, 44% of IHC negative cases became positive while 36% of the positive IHC cases became negative by alternative FISH testing. Available data showed that 41% of patients were treated with palbociclib and were positive by alternative FISH.
CONCLUSION: The prevalence of double HER2 equivocal cases and the discrepancy between IHC and alternative FISH testing suggest that FISH alternative testing using both RAI1 and TP53 probes is necessary for conclusive classification. Because almost half of FISH equivocal cases converted to HER2 amplified upon alternative testing, clinical studies to determine the benefit of anti-HER2 therapy in these patients are urgently needed.

Dou M, Zhou X, Fan Z, et al.
Clinical Significance of Retinoic Acid Receptor Beta Promoter Methylation in Prostate Cancer: A Meta-Analysis.
Cell Physiol Biochem. 2018; 45(6):2497-2505 [PubMed] Related Publications
BACKGROUND/AIMS: Retinoic acid receptor beta (RAR beta) is a retinoic acid receptor gene that has been shown to play key roles during multiple cancer processes, including cell proliferation, apoptosis, migration and invasion. Numerous studies have found that methylation of the RAR beta promoter contributed to the occurrence and development of malignant tumors. However, the connection between RAR beta promoter methylation and prostate cancer (PCa) remains unknown. This meta-analysis evaluated the clinical significance of RAR beta promoter methylation in PCa.
MATERIALS AND METHODS: We searched all published records relevant to RAR beta and PCa in a series of databases, including PubMed, Embase, Cochrane Library, ISI Web of Science and CNKI. The rates of RAR beta promoter methylation in the PCa and control groups (including benign prostatic hyperplasia and normal prostate tissues) were summarized. In addition, we evaluated the source region of available samples and the methods used to detect methylation. To compare the incidence and variation in RAR beta promoter methylation in PCa and non-PCa tissues, the odds ratio (OR) and 95% confidence interval (CI) were calculated accordingly. All the data were analyzed with the statistical software STATA 12.0.
RESULTS: Based on the inclusion and exclusion criteria, 15 articles assessing 1,339 samples were further analyzed. These data showed that the RAR beta promoter methylation rates in PCa tissues were significantly higher than the rates in the non-PCa group (OR=21.65, 95% CI: 9.27-50.57). Subgroup analysis according to the source region of samples showed that heterogeneity in Asia was small (I2=0.0%, P=0.430). Additional subgroup analysis based on the method used to detect RAR beta promoter methylation showed that the heterogeneity detected by MSP (methylation-specific PCR) was relatively small (I2=11.3%, P=0.343).
CONCLUSION: Although studies reported different rates for RAR beta promoter methylation in PCa tissues, the total analysis demonstrated that RAR beta promoter methylation may be correlated with PCa carcinogenesis and that the RAR beta gene is particularly susceptible. Additional studies with sufficient data are essential to further evaluate the clinical features and prognostic utility of RAR beta promoter methylation in PCa.

Coccaro N, Zagaria A, Orsini P, et al.
RARA and RARG gene downregulation associated with EZH2 mutation in acute promyelocytic-like morphology leukemia.
Hum Pathol. 2018; 80:82-86 [PubMed] Related Publications
Most acute promyelocytic leukemia (APL) patients express PML-RARA fusion; in rare cases, RARA is rearranged with partner genes other than PML. To date, only 2 patients presenting features similar to APL showing the RARG gene rearrangement have been described. We report an acute myeloid leukemia patient with morphology resembling APL without involvement of the RARA gene. Molecular and fluorescent in situ hybridization analyses excluded PML-RARA fusion and variant rearrangements involving RARA and RARG loci. Targeted next-generation sequencing showed EZH2- D185H mutation. As this mutation involved the region of interaction with DNA methyltransferases, we speculate an epigenetic alteration of genes involved in the APL-like phenotype. Expression analysis by droplet digital polymerase chain reaction revealed downregulation of the RARA and RARG genes. We hypothesize a novel mechanism of EZH2 function alteration, which may be responsible for an acute myeloid leukemia with APL-like phenotype featuring dysregulation of the RARA and RARG genes.

Infante Lara L, Fenner S, Ratcliffe S, et al.
Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences.
Nucleic Acids Res. 2018; 46(5):2218-2233 [PubMed] Free Access to Full Article Related Publications
Etoposide and other topoisomerase II-targeted drugs are important anticancer therapeutics. Unfortunately, the safe usage of these agents is limited by their indiscriminate induction of topoisomerase II-mediated DNA cleavage throughout the genome and by a lack of specificity toward cancer cells. Therefore, as a first step toward constraining the distribution of etoposide-induced DNA cleavage sites and developing sequence-specific topoisomerase II-targeted anticancer agents, we covalently coupled the core of etoposide to oligonucleotides centered on a topoisomerase II cleavage site in the PML gene. The initial sequence used for this 'oligonucleotide-linked topoisomerase inhibitor' (OTI) was identified as part of the translocation breakpoint of a patient with acute promyelocytic leukemia (APL). Subsequent OTI sequences were derived from the observed APL breakpoint between PML and RARA. Results indicate that OTIs can be used to direct the sites of etoposide-induced DNA cleavage mediated by topoisomerase IIα and topoisomerase IIβ. OTIs increased levels of enzyme-mediated cleavage by inhibiting DNA ligation, and cleavage complexes induced by OTIs were as stable as those induced by free etoposide. Finally, OTIs directed against the PML-RARA breakpoint displayed cleavage specificity for oligonucleotides with the translocation sequence over those with sequences matching either parental gene. These studies demonstrate the feasibility of using oligonucleotides to direct topoisomerase II-mediated DNA cleavage to specific sites in the genome.

Mason EF, Kuo FC, Hasserjian RP, et al.
A distinct immunophenotype identifies a subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome.
Am J Hematol. 2018; 93(4):504-510 [PubMed] Related Publications
Recent work has identified distinct molecular subgroups of acute myeloid leukemia (AML) with implications for disease classification and prognosis. NPM1 is one of the most common recurrently mutated genes in AML. NPM1 mutations often co-occur with FLT3-ITDs and mutations in genes regulating DNA methylation, such as DNMT3A, TET2, and IDH1/2. It remains unclear whether these genetic alterations are associated with distinct immunophenotypic findings or affect prognosis. We identified 133 cases of NPM1-mutated AML and correlated sequencing data with immunophenotypic and clinical findings. Of 84 cases (63%) that lacked monocytic differentiation ("myeloid AML"), 40 (48%) demonstrated an acute promyelocytic leukemia-like (APL-like) immunophenotype by flow cytometry, with absence of CD34 and HLA-DR and strong myeloperoxidase expression, in the absence of a PML-RARA translocation. Pathologic variants in TET2, IDH1, or IDH2 were identified in 39/40 APL-like cases. This subset of NPM1-mutated AML was associated with longer relapse-free and overall survival, when compared with cases that were positive for CD34 and/or HLA-DR. The combination of NPM1 and TET2 or IDH1/2 mutations along with an APL-like immunophenotype identifies a distinct subtype of AML. Further studies addressing its biology and clinical significance may be especially relevant in the era of IDH inhibitors and recent work showing efficacy of ATRA therapy in NPM1 and IDH1-mutated AML.

Fischer-Huchzermeyer S, Dombrowski A, Wilke G, et al.
MEK inhibitors enhance therapeutic response towards ATRA in NF1 associated malignant peripheral nerve sheath tumors (MPNST) in-vitro.
PLoS One. 2017; 12(11):e0187700 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome characterized by an increased risk of malignant peripheral nerve sheath tumors (MPNST). Chemotherapy of MPNST is still insufficient. In this study, we investigated whether human tumor Schwann cells derived from NF1 associated MPNST respond to all-trans retinoic acid (ATRA). We analyzed effects of ATRA and MEK inhibitor (MEKi) combination therapy.
METHODS: MPNST cell lines S462, T265, NSF1 were treated with ATRA and MEKi U0126 and PD0325901. We assessed cell viability, proliferation, migration, apoptosis and differentiation as well as mRNA expression of RAR and RXR subtypes and ATRA target genes such as CRABP2, CYP26A1, RARB and PDK1. We also analyzed CRABP2 methylation in cell lines and performed immunohistochemistry of human MPNST specimens.
RESULTS: ATRA therapy reduced viability and proliferation in S462 and T265 cells, accompanied by differentiation, apoptosis and reduced migration. NSF1 cells which lacked RXRG expression did not respond to ATRA. We furthermore demonstrated that ATRA signaling was functional for common targets, and that mRNA expression of CRABP2 and its targets was raised by ATRA therapy, whereas alternative pathways via FABP5 were not induced. Finally, combination of ATRA and MEKi demonstrated additively reduced viability of T265 and S462 cells.
CONCLUSIONS: We observed therapeutic effects in two of three MPNST cell lines pronounced by combination therapy. These data point to a potentially successful treatment of MPNST by combined application of ATRA and MEK inhibitors such as U0126 or PD0325901.

Iijima-Yamashita Y, Matsuo H, Yamada M, et al.
Multiplex fusion gene testing in pediatric acute myeloid leukemia.
Pediatr Int. 2018; 60(1):47-51 [PubMed] Related Publications
BACKGROUND: Gene abnormalities, particularly chromosome rearrangements generating gene fusion, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification, but the results are not always consistent with those of reverse transcription-polymerase chain reaction (RT-PCR), and more accurate and rapid methods are required.
METHODS: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and from acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation. Multiplex quantitative RT-PCR was performed to detect eight important fusion genes: AML1(RUNX1)-ETO(RUNX1T1), CBFB-MYH11, MLL(KMT2A)-AF9(MLLT3), MLL-ELL, MLL-AF6(MLLT4), FUS(TLS)-ERG, NUP98-HOXA9, and PML-RARA.
RESULTS: Fusion genes were detected in 207 (46.2%) of the 448 AML-05 patient samples. After exclusion of two samples with PML-RARA, no chromosomal abnormalities were identified on karyotyping in 19 of 205 patients (9.3%) positive for fusion genes on RT-PCR. Fusion genes were confirmed on fluorescence in situ hybridization (FISH) in 11 of these 19 patients. In contrast, fusion genes were detected in 37 of 39 patients (94.9%) from the AML-P05 study, and 33 of these results were consistent with the karyotyping. There were discrepancies in four patients (10.8%), three with normal karyotypes and one in whom karyotyping was not possible. All four of these patients were PML-RARA positive on FISH.
CONCLUSIONS: Multiplex quantitative RT-PCR-based fusion gene screening may be effective for diagnosis of pediatric AML.

Schläfli AM, Isakson P, Garattini E, et al.
The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells.
Sci Rep. 2017; 7(1):12980 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) is a malignancy of myeloid progenitor cells that are blocked in differentiation. Acute promyelocytic leukemia (APL) is a rare form of AML, which generally presents with a t(15;17) translocation causing expression of the fusion protein PML-RARA. Pharmacological doses of all-trans retinoic acid (ATRA) induce granulocytic differentiation of APL cells leading to cure rates of >80% if combined with conventional chemotherapy. Autophagy is a lysosomal degradation pathway for the removal of cytoplasmic content and recycling of macromolecules. ATRA induces autophagy in ATRA-sensitive AML and APL cells and autophagy inhibition attenuates ATRA-triggered differentiation. In this study, we aimed at identifying if the autophagy-linked FYVE-domain containing protein (ALFY/WDFY3) is involved in autophagic degradation of protein aggregates contributes to ATRA therapy-induced autophagy. We found that ALFY mRNA levels increase significantly during the course of ATRA-induced differentiation of APL and AML cell lines. Importantly ALFY depletion impairs ATRA-triggered granulocytic differentiation of these cells. In agreement with its function in aggrephagy, knockdown of ALFY results in reduced ATRA-induced proteolysis. Our data further suggest that PML-RARα is an autophagy substrate degraded with the help of ALFY. In summary, we present a crucial role for ALFY in retinoid triggered maturation of AML cells.

Youn H, Lee HK, Sohn HR, et al.
RaRF confers RA resistance by sequestering RAR to the nucleolus and regulating MCL1 in leukemia cells.
Oncogene. 2018; 37(3):352-362 [PubMed] Related Publications
Retinoic acid (RA) has broad clinical applications for the treatment of various cancers, particularly acute promyelocytic leukemia. However, RA-based therapy is limited by relapse in patients associated with RA resistance, the mechanism of which is poorly understood. Here, we suggest a new molecular mechanism of RA resistance by a repressor, named RA resistance factor (RaRF). RaRF suppressed transcriptional activity of the RA receptor (RAR) by directly interacting with and sequestering RAR to the nucleolus in response to RA. RaRF was highly expressed in RA-resistant leukemia cells and its expression was strongly correlated with RA sensitivity. MCL1 was upregulated by RA treatment upon RaRF depletion, accompanying leukemic myeloblast differentiation, which is negatively regulated by ectopic RaRF expression. Collectively, we propose that RaRF may be a factor in the resistance mechanism and thus a potential target for leukemia therapy using RA.

Yamamoto M, Ikuta K, Toki Y, et al.
Angioimmunoblastic T-cell lymphoma and hypereosinophilic syndrome with FIP1L1/PDGFRA fusion gene effectively treated with imatinib: A case report.
Medicine (Baltimore). 2017; 96(36):e8001 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and organ damage. Some cases of HES are caused by the FIP1L1/PDGFRA fusion gene and respond to imatinib. FIP1L1/PDGFRA-positive HES occasionally evolves into chronic eosinophilic leukemia or into another form of myeloproliferative neoplasm; however, the development of a malignant lymphoma is very rare. We present a rare case of angioimmunoblastic T-cell lymphoma (AITL) and HES with the FIP1L1/PDGFRA gene rearrangement.
PATIENT CONCERNS: A man in his 30s presented to our hospital with fever, hypereosinophilia, widespread lymphadenopathy, and splenomegaly. Laboratory tests showed hypereosinophilia, increased soluble interleukin-2 receptor, and increased vitamin B12. Positron-emission tomography with F fluorodeoxyglucose (FDG) showed positive FDG uptake in multiple enlarged lymph nodes throughout the body and the red bone marrow. A bone-marrow biopsy showed hypereosinophilia without dysplasia and an increased number of blasts. The FIP1L1/PDGFRA fusion gene was positive upon fluorescence in situ hybridization (FISH) analysis of the peripheral blood. Furthermore, biopsy of a lymph node from the neck revealed restiform hyperplasia of capillary vessels, with small lymphoma cells arranged around the capillaries. Lymphoma cells were positive for CD3, CD4, and CD10, and negative for CD20. Lymphoma cells were also positive for the FIP1L1/PDGFRA fusion gene by FISH analysis.
DIAGNOSES: From these findings, the patient was diagnosed with HES and AITL with FIP1L1/PDGFRA.
INTERVENTIONS: After the diagnosis, corticosteroid was administered but was ineffective. Imatinib was then administered.
OUTCOMES: Imatinib was very effective for treating HES and AITL, and complete remission was achieved in both.
LESSONS: This report presents the first case in which the FIP1L1/PDGFRA fusion gene was positive both in peripheral blood and lymph nodes, implying the possibility that the tumor cells acquired the FIP1L1/PDGFRA fusion gene in the early stage of hematopoietic progenitor cell developments. Imatinib was very effective in treating both HES and lymphoma, suggesting that the FIP1L1/PDGFRA fusion gene plays a key role in the pathogenesis of both HES and lymphoma.

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