ZBTB16

Gene Summary

Gene:ZBTB16; zinc finger and BTB domain containing 16
Aliases: PLZF, ZNF145
Location:11q23.1
Summary:This gene is a member of the Krueppel C2H2-type zinc-finger protein family and encodes a zinc finger transcription factor that contains nine Kruppel-type zinc finger domains at the carboxyl terminus. This protein is located in the nucleus, is involved in cell cycle progression, and interacts with a histone deacetylase. Specific instances of aberrant gene rearrangement at this locus have been associated with acute promyelocytic leukemia (APL). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:zinc finger and BTB domain-containing protein 16
HPRD
Source:NCBIAccessed: 18 March, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 18 March 2015 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.

  • Leukemia, Promyelocytic, Acute
  • Molecular Sequence Data
  • Transcription Factors
  • Zinc Fingers
  • Apoptosis
  • Kruppel-Like Transcription Factors
  • Neoplasm Proteins
  • RTPCR
  • Repressor Proteins
  • siRNA
  • Western Blotting
  • Cell Differentiation
  • Acute Myeloid Leukaemia
  • Tumor Suppressor Proteins
  • Leukemic Gene Expression Regulation
  • Polymerase Chain Reaction
  • Homeodomain Proteins
  • Cell Cycle
  • Proto-Oncogene Proteins
  • Retinoic Acid
  • Electrophoretic Mobility Shift Assay
  • Oligonucleotide Array Sequence Analysis
  • Chromosome 17
  • DNA-Binding Proteins
  • Cell Proliferation
  • Childhood Cancer
  • Nuclear Proteins
  • Messenger RNA
  • Protein Binding
  • Translocation
  • Gene Expression Profiling
  • RARA
  • Promoter Regions
  • Base Sequence
  • Neoplastic Cell Transformation
  • Chromosome 11
  • Cancer Gene Expression Regulation
  • Oncogene Fusion Proteins
  • Receptors, Retinoic Acid
  • Drug Resistance
  • Binding Sites
Tag cloud generated 18 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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

Entity Topic PubMed Papers
Acute Myeloid Leukaemia (AML)t(11;17)(q32;q21) RARA-PLZF in Acute Promyelocytic Leukemia

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

Latest Publications: ZBTB16 (cancer-related)

Choi WI, Kim MY, Jeon BN, et al.
Role of promyelocytic leukemia zinc finger (PLZF) in cell proliferation and cyclin-dependent kinase inhibitor 1A (p21WAF/CDKN1A) gene repression.
J Biol Chem. 2014; 289(27):18625-40 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Promyelocytic leukemia zinc finger (PLZF) is a transcription repressor that was initially isolated as a fusion protein with retinoic acid receptor α. PLZF is aberrantly overexpressed in various human solid tumors, such as clear cell renal carcinoma, glioblastoma, and seminoma. PLZF causes cellular transformation of NIH3T3 cells and increases cell proliferation in several cell types. PLZF also increases tumor growth in the mouse xenograft tumor model. PLZF may stimulate cell proliferation by controlling expression of the genes of the p53 pathway (ARF, TP53, and CDKN1A). We found that PLZF can directly repress transcription of CDKN1A encoding p21, a negative regulator of cell cycle progression. PLZF binds to the proximal Sp1-binding GC-box 5/6 and the distal p53-responsive elements of the CDKN1A promoter to repress transcription. Interestingly, PLZF interacts with Sp1 or p53 and competes with Sp1 or p53. PLZF interacts with corepressors, such as mSin3A, NCoR, and SMRT, thereby deacetylates Ac-H3 and Ac-H4 histones at the CDKN1A promoter, which indicated the involvement of the corepressor·HDACs complex in transcription repression by PLZF. Also, PLZF represses transcription of TP53 and also decreases p53 protein stability by ubiquitination. PLZF may act as a potential proto-oncoprotein in various cell types.

Dorantes-Acosta E, Medina-Sanson A, Jaimes-García Y, López-Martínez B
Clinical features and treatment outcomes of pediatric acute promyelocytic leukemia in a Mexican pediatric hospital.
Rev Invest Clin. 2013 Sep-Oct; 65(5):392-8 [PubMed] Related Publications
INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia (AML) characterized by chromosomal translocations involving the retinoid acid receptor α (RARA) gene on chromosome 17. APL is a relatively rare blood disease that is highly curable with current treatment strategies; however, patient outcomes are heterogeneous in countries with limited resources. Promyelocytic leukemia accounts for 20-25% of all AML cases in Latin American countries.
MATERIAL AND METHODS: We conducted a study from July 2007 to July 2012 and applied the IC-APL2006 protocol. This case study reports the results from eleven patients with AML M3 (five males and six females). In all cases, the diagnoses were made by aspirating bone marrow and evaluating the t(15:17) or t(11:17) transcript. In eight cases, the molecular biology-based diagnostics for the PLM-RARa transcript were positive, and they were negative in two cases. One patient was positive for the PLZF-RARa transcript.
RESULTS: The mean WBC at the time of diagnosis was 10.1 x 10(9)/L, and the mean platelet count was 17.1 x 10(9)/L. The mean percentage of abnormal promyelocytes in the bone marrow aspirates was 68%. Of the eleven patients, four presented with disseminated intravascular coagulation. All of the patients began treatment with transretinoic acid (ATRA) (45 mg/m(2)/day), which led to 4 cases of ATRA syndrome. There were 2 relapses, and the patient died in one case. The remaining ten patients were alive after the median follow-up period of 33.6 months (range from 11 to 60 months).
CONCLUSION: The authors report on a series of cases involving pediatric patients with AML M3 seen at a single institution; the patients were stratified and treated with a standard protocol to obtain satisfactory results. Although the number of patients is limited, the health outcomes are relevant. To our knowledge, this is the first series of pediatric APL patients in Mexico who were treated with the IC-APL2006 protocol.

Qiu M, Bao W, Wang J, et al.
FOXA1 promotes tumor cell proliferation through AR involving the Notch pathway in endometrial cancer.
BMC Cancer. 2014; 14:78 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
BACKGROUND: Increasing evidence suggests that forkhead box A1 (FOXA1) is frequently dysregulated in many types of human cancers. However, the exact function and mechanism of FOXA1 in human endometrial cancer (EC) remains unclear.
METHODS: FOXA1 expression, androgen receptor (AR) expression, and the relationships of these two markers with clinicopathological factors were determined by immunohistochemistry analysis. FOXA1 and AR were up-regulated by transient transfection with plasmids, and were down-regulated by transfection with siRNA or short hairpin RNA (shRNA). The effects of FOXA1 depletion and FOXA1 overexpression on AR-mediated transcription as well as Notch pathway and their impact on EC cell proliferation were examined by qRT-PCR, western blotting, co-immunoprecipitation, ChIP-PCR, MTT, colony-formation, and xenograft tumor-formation assays.
RESULTS: We found that the expression of FOXA1 and AR in ECs was significantly higher than that in a typical hyperplasia and normal tissues. FOXA1 expression was significantly correlated with AR expression in clinical tissues. High FOXA1 levels positively correlated with pathological grade and depth of myometrial invasion in EC. High AR levels also positively correlated with pathological grade in EC. Moreover, the expression of XBP1, MYC, ZBTB16, and UHRF1, which are downstream targets of AR, was promoted by FOXA1 up-regulation or inhibited by FOXA1 down-regulation. Co-immunoprecipitation showed that FOXA1 interacted with AR in EC cells. ChIP-PCR assays showed that FOXA1 and AR could directly bind to the promoter and enhancer regions upstream of MYC. Mechanistic investigation revealed that over-expression of Notch1 and Hes1 proteins by FOXA1 could be reversed by AR depletion. In addition, we showed that down-regulation of AR attenuated FOXA1-up-regulated cell proliferation. However, AR didn't influence the promotion effect of FOXA1 on cell migration and invasion. In vivo xenograft model, FOXA1 knockdown reduced the rate of tumor growth.
CONCLUSIONS: These results suggest that FOXA1 promotes cell proliferation by AR and activates Notch pathway. It indicated that FOXA1 and AR may serve as potential gene therapy in EC.

Mariani F, Sena P, Magnani G, et al.
PLZF expression during colorectal cancer development and in normal colorectal mucosa according to body size, as marker of colorectal cancer risk.
ScientificWorldJournal. 2013; 2013:630869 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Promyelocytic leukemia zinc finger protein (PLZF) is a protein involved in various signaling, growth regulatory, and differentiation pathways, including development/function of some T cells. Here, we aimed at the detection of PLZF during colorectal carcinogenesis, using immunofluorescence, and at the evaluation of the colocalization of PLZF with CD2 and CD56 positive cells (T, γ δ , NK, and NKT cells), using confocal-microscopy, along colorectal carcinogenesis, since its earliest stages, that is, dysplastic aberrant crypt foci (ACF). Furthermore, we analyzed PLZF in the normal colonic mucosa (NM) according to anthropometric parameters of the subject. NM exhibited strong CD56 fluorescent staining. This infiltration was lost in both ACF and colorectal carcinoma (CRC), while PLZF presence increased from NM to ACF and CRC. Strong association was found between CD56+ colonic mucosa cell infiltration and body mass index. Interestingly, an increased stromal PLZF-reactivity was present in NM of obese subjects. This study shows that overexpression of PLZF and exclusion of NK cells in dysplastic microenvironment are very early events in the stepwise sequence leading to CRC and that lower levels of CD56+ cells in NM, together with increased levels of PLZF+ cells, can be a reflection of colon cancer risk due to obesity.

Cao J, Zhu S, Zhou W, et al.
PLZF mediates the PTEN/AKT/FOXO3a signaling in suppression of prostate tumorigenesis.
PLoS One. 2013; 8(12):e77922 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Promyelocytic leukemia zinc finger (PLZF) protein expression is closely related to the progression of human cancers, including prostate cancer (PCa). However, the according context of a signaling pathway for PLZF to suppress prostate tumorigenesis remains greatly unknown. Here we report that PLZF is a downstream mediator of the PTEN signaling pathway in PCa. We found that PLZF expression is closely correlated with PTEN expression in a cohort of prostate cancer specimens. Interestingly, both PTEN rescue and phosphoinositide 3-kinase (PI3K) inhibitor LY294002 treatment increase the PLZF expression in prostate cancer cell lines. Further, luciferase reporter assay and chromatin immunoprecipitation assay demonstrate that FOXO3a, a transcriptional factor phosphorylated by PI3K/AKT, could directly bind to the promoter of PLZF gene. These results indicate that PTEN regulates PLZF expression by AKT/FOXO3a. Moreover, our animal experiments also demonstrate that PLZF is capable of inhibiting prostate tumorigenesis in vivo. Taken together, our study defines a PTEN/PLZF pathway and would shed new lights for developing therapeutic strategy of prostate cancer.

Girard N, Tremblay M, Humbert M, et al.
RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells.
Proc Natl Acad Sci U S A. 2013; 110(33):13522-7 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.

Ono R, Masuya M, Nakajima H, et al.
Plzf drives MLL-fusion-mediated leukemogenesis specifically in long-term hematopoietic stem cells.
Blood. 2013; 122(7):1271-83 [PubMed] Related Publications
Oncogenic transformation requires unlimited self-renewal. Currently, it remains unclear whether a normal capacity for self-renewal is required for acquiring an aberrant self-renewal capacity. Our results in a new conditional transgenic mouse showed that a mixed lineage leukemia (MLL) fusion oncogene, MLL-ENL, at an endogenous-like expression level led to leukemic transformation selectively in a restricted subpopulation of hematopoietic stem cells (HSCs) through upregulation of promyelocytic leukemia zinc finger (Plzf). Interestingly, forced expression of Plzf itself immortalized HSCs and myeloid progenitors in vitro without upregulation of Hoxa9/Meis1, which are well-known targets of MLL fusion proteins, whereas its mutant lacking the BTB/POZ domain did not. In contrast, depletion of Plzf suppressed the MLL-fusion-induced leukemic transformation of HSCs in vitro and in vivo. Gene expression analyses of human clinical samples showed that a subtype of PLZF-high MLL-rearranged myeloid leukemia cells was closely associated with the gene expression signature of HSCs. These findings suggested that MLL fusion protein enhances the self-renewal potential of normal HSCs to develop leukemia, in part through a Plzf-driven self-renewal program.

Wang X, Wang L, Guo S, et al.
Hypermethylation reduces expression of tumor-suppressor PLZF and regulates proliferation and apoptosis in non-small-cell lung cancers.
FASEB J. 2013; 27(10):4194-203 [PubMed] Related Publications
Deregulation of promyelocytic leukemia zinc finger protein (PLZF), a tumor suppressor gene, was reported in different types of solid tumors. This study for the first time explored the reduced expression of PLZF and its effects in non-small-cell lung cancer (NSCLC) carcinogenesis. PLZF was found to be down-regulated by 62.8% in 87.1% of 154 paired NSCLC samples by quantitative real-time PCR, and its expression was found to be associated with the sex of the patient (P=0.02). Further analysis showed that down-regulation of PLZF in 35.6% NSCLC samples (31 out of 87) was triggered by hypermethylation in the promoter region. This was validated by demethylation analysis using the A549 cell line. Dual-luciferase reporter assay indicated that CTCF binding to the promoter region could activate PLZF transcription. Overexpression of PLZF in both A549 and LTEP lung cancer cell lines was found to inhibit proliferation and increase apoptosis. Therefore, reduced expression of PLZF was found to be common in NSCLC. PLZF down-regulation was partially correlated with hypermethylation in the promoter region. Decreased levels of PLZF expression may contribute to the pathogenesis of NSCLC by promoting cell survival. Therefore, the restoration of PLZF expression may serve as a new strategy for NSCLC therapy.

Jin Y, Qu S, Tesikova M, et al.
Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer.
Proc Natl Acad Sci U S A. 2013; 110(28):E2572-81 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major proliferative pathways in a number of tissues and are the main therapeutic targets in various disorders, including prostate cancer (PCa). Previous work has shown that there is reciprocal feedback regulation of PI3K and AR signaling in PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. Here we show that proteins encoded by two androgen-regulated genes, kallikrein related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 interacts with PLZF and decreases its stability. PLZF in turn interacts with AR and inhibits its function as a transcription factor. PLZF also activates expression of regulated in development and DNA damage responses 1, an inhibitor of mTORC1. Thus, a unique molecular switch is generated that regulates both AR and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent growth, induces apoptosis, and dramatically sensitizes PCa cells to apoptosis-inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery in mice bearing PCa tumors results in profound remission. These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy.

Petruccelli LA, Pettersson F, Del Rincón SV, et al.
Expression of leukemia-associated fusion proteins increases sensitivity to histone deacetylase inhibitor-induced DNA damage and apoptosis.
Mol Cancer Ther. 2013; 12(8):1591-604 [PubMed] Related Publications
Histone deacetylase inhibitors (HDI) show activity in a broad range of hematologic and solid malignancies, yet the percentage of patients in any given malignancy who experience a meaningful clinical response remains small. In this study, we sought to investigate HDI efficacy in acute myeloid leukemia (AML) cells expressing leukemia-associated fusion proteins (LAFP). HDIs have been shown to induce apoptosis, in part, through accumulation of DNA damage and inhibition of DNA repair. LAFPs have been correlated with a DNA repair-deficient phenotype, which may make them more sensitive to HDI-induced DNA damage. We found that expression of the LAFPs PLZF-RARα, PML-RARα, and RUNX1-ETO (AML1-ETO) increased sensitivity to DNA damage and apoptosis induced by the HDI vorinostat. The increase in apoptosis correlated with an enhanced downregulation of the prosurvival protein BCL2. Vorinostat also induced expression of the cell-cycle regulators p19(INK4D) and p21(WAF1) and triggered a G2-M cell cycle arrest to a greater extent in LAFP-expressing cells. The combination of LAFP and vorinostat further led to a greater downregulation of several base excision repair (BER) enzymes. These BER genes represent biomarker candidates for response to HDI-induced DNA damage. Notably, repair of vorinostat-induced DNA double-strand breaks was found to be impaired in PLZF-RARα-expressing cells, suggesting a mechanism by which LAFP expression and HDI treatment cooperate to cause an accumulation of damaged DNA. These data support the continued study of HDI-based treatment regimens in LAFP-positive AMLs.

Zaade D, Schmitz J, Benke E, et al.
Distinct signal transduction pathways downstream of the (P)RR revealed by microarray and ChIP-chip analyses.
PLoS One. 2013; 8(3):e57674 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
The (pro)renin receptor ((P)RR) signaling is involved in different pathophysiologies ranging from cardiorenal end-organ damage via diabetic retinopathy to tumorigenesis. We have previously shown that the transcription factor promyelocytic leukemia zinc finger (PLZF) is an adaptor protein of the (P)RR. Furthermore, recent publications suggest that major functions of the (P)RR are mediated ligand-independently by its transmembrane and intracellular part, which acts as an accessory protein of V-ATPases. The transcriptome and recruitmentome downstream of the V-ATPase function and PLZF in the context of the (P)RR are currently unknown. Therefore, we performed a set of microarray and chromatin-immunoprecipitation (ChIP)-chip experiments using siRNA against the (P)RR, stable overexpression of PLZF, the PLZF translocation inhibitor genistein and the specific V-ATPase inhibitor bafilomycin to dissect transcriptional pathways downstream of the (P)RR. We were able to identify distinct and overlapping genetic signatures as well as novel real-time PCR-validated target genes of the different molecular functions of the (P)RR. Moreover, bioinformatic analyses of our data confirm the role of (P)RŔs signal transduction pathways in cardiovascular disease and tumorigenesis.

Hechtman JF, Beasley MB, Kinoshita Y, et al.
Promyelocytic leukemia zinc finger and histone H1.5 differentially stain low- and high-grade pulmonary neuroendocrine tumors: a pilot immunohistochemical study.
Hum Pathol. 2013; 44(7):1400-5 [PubMed] Related Publications
Promyelocytic leukemia zinc finger is a zinc finger transcription factor that functions as a transcriptional repressor. Its expression has been shown to be down-regulated in hematopoietic, melanocytic, and mesothelial malignancies. Histone H1.5 is a variant of histone H1, a family of linker proteins that organizes chromosomes into higher order structures. Its function is of key importance in gene expression and has been linked to more aggressive forms of prostatic carcinoma. This study aimed to investigate the immunohistochemical detectability of promyelocytic leukemia zinc finger and histone H1.5 in pulmonary neuroendocrine tumors, comprising 11 carcinoid tumorlets, 24 typical carcinoids, 12 atypical carcinoids, 20 small cell carcinomas, 11 large cell neuroendocrine carcinomas, and 2 combined small cell carcinomas-large cell neuroendocrine carcinomas. Promyelocytic leukemia zinc finger immunohistochemistry revealed moderate or strong nuclear staining in all carcinoid tumorlets, 23 of 24 typical carcinoids, and 7 of 12 atypical carcinoids in contrast to 9 of 11 large cell neuroendocrine carcinomas, all small cell carcinoma, and both combined small cell carcinoma-large cell neuroendocrine carcinomas, which showed no nuclear immunoreactivity. Histone H1.5 immunohistochemistry revealed only focal or no immunoreactivity in all carcinoid tumorlets and 19 of 24 typical carcinoids, whereas 7 of 12 atypical carcinoids, 19 of 20 small cell carcinomas, 10 of 11 large cell neuroendocrine carcinomas, and both combined small cell carcinomas-large cell neuroendocrine carcinomas displayed positive (≥ 10%) nuclear immunoreactivity-ranging from a minority of weak staining to a majority of strong staining cases. Our data suggest that the relative expression ratios of promyelocytic leukemia zinc finger and histone H1.5 may correlate with grade of pulmonary neuroendocrine tumors. Immunohistochemical stains for these markers, especially on small biopsies with crush artifact, may prove to be diagnostically useful.

Jiao B, Ren ZH, Liu P, et al.
8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation.
Proc Natl Acad Sci U S A. 2013; 110(9):3495-500 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
The refractoriness of acute promyelocytic leukemia (APL) with t(11;17)(q23;q21) to all-trans retinoic acid (ATRA)-based therapy concerns clinicians and intrigues basic researchers. By using a murine leukemic model carrying both promyelocytic leukemia zinc finger/retinoic acid receptor-α (PLZF/RARα) and RARα/PLZF fusion genes, we discovered that 8-chlorophenylthio adenosine-3', 5'-cyclic monophosphate (8-CPT-cAMP) enhances cellular differentiation and improves gene trans-activation by ATRA in leukemic blasts. Mechanistically, in combination with ATRA, 8-CPT-cAMP activates PKA, causing phosphorylation of PLZF/RARα at Ser765 and resulting in increased dissociation of the silencing mediator for retinoic acid and thyroid hormone receptors/nuclear receptor corepressor from PLZF/RARα. This process results in changes of local chromatin and transcriptional reactivation of the retinoic acid pathway in leukemic cells. Meanwhile, 8-CPT-cAMP also potentiated ATRA-induced degradation of PLZF/RARα through its Ser765 phosphorylation. In vivo treatment of the t(11;17) APL mouse model demonstrated that 8-CPT-cAMP could significantly improve the therapeutic effect of ATRA by targeting a leukemia-initiating cell activity. This combined therapy, which induces enhanced differentiation and oncoprotein degradation, may benefit t(11;17) APL patients.

Wei C, Sirikanjanapong S, Lieberman S, et al.
Primary mucosal melanoma arising from the eustachian tube with CTLA-4, IL-17A, IL-17C, and IL-17E upregulation.
Ear Nose Throat J. 2013; 92(1):36-40 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Primary malignant melanoma arising from the eustachian tube is extremely rare. We report the case of a 63-year-old white man who presented with a 1-month history of left-sided hearing loss and aural fullness. Flexible fiberoptic laryngoscopy detected a blue-purple mass that appeared to arise from the left lateral nasopharynx. Computed tomography demonstrated an enhancing mass arising from an orifice of the left eustachian tube. The tumor was debulked endoscopically and was confirmed to have originated in the left eustachian tube. Histologically, the tumor was made up of heavily pigmented pleomorphic spindle cells with frequent mitoses. The tumor cells were immunohistochemically positive for S-100 protein, HMB-45, Melan-A, and PNL-2. The final diagnosis was a mucosal malignant melanoma. We also performed a nested polymerase chain reaction assay for several genes of interest, including CTLA-4, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, PLZF, Foxp3, RORγt, CD27, and CD70. These genes have been studied mainly in cutaneous melanomas, especially for the development of immunotherapy, but only very limited studies have been done on mucosal melanomas. Our investigation found upregulation of CTLA-4, IL-17A, IL-17C, and IL-17E. Based on our finding of CTLA-4 upregulation, it may be suggested that our patient might have had low antitumor immunity and that he might have benefited from CTLA-4 blockade. On the other hand, upregulation of IL-17A and IL-17E might reflect increased antitumor immunity, which could suggest that patients with a mucosal melanoma might benefit from immunomodulators associated with the effect of Th17. These genes also have great potential to help melanoma patients obtain tailored treatment, and they can be used as biomarkers for predicting prognosis.

Yang WC, Shih HM
The deubiquitinating enzyme USP37 regulates the oncogenic fusion protein PLZF/RARA stability.
Oncogene. 2013; 32(43):5167-75 [PubMed] Related Publications
Acute promyelocytic leukemia (APL) is predominantly characterized by chromosomal translocations between the retinoic acid receptor, alpha (RARA) gene and the promyelocytic leukemia (PML) or promyelocytic leukemia zinc finger (PLZF) gene. In APL cells with PML/RARA fusions, arsenic trioxide and all-trans retinoic acid treatments specifically target the fusion protein for proteasome-dependent degradation, thereby promoting cellular differentiation and clinical remission of disease. In contrast, APL cells expressing PLZF/RARA fusion proteins are largely resistant to similar treatments and prognosis for patients with this translocation is poor. Understanding the molecular mechanisms regulating PLZF/RARA protein stability would provide novel therapeutic targets for PLZF/RARA-associated APL. Toward this end, we have performed an RNAi-based screen to identify factors affecting PLZF/RARA stability. Among the factors identified was the ubiquitin-specific peptidase 37 (USP37). We showed that USP37 interacted with PLZF/RARA through the PLZF moiety and sustained PLZF/RARA steady state levels. Domain mapping study revealed that N-terminal domain of USP37 is required for the PLZF/RARA interaction and protein regulation. Furthermore, overexpression or depletion of USP37 caused an increase or decrease of PLZF/RARA protein half-life, correlating with down- or upregulation of PLZF/RARA poly-ubiquitination, respectively. By PLZF/RARA-transduced primary mouse hematopoietic progenitor cells, we demonstrated that Usp37 knockdown alleviated PLZF/RARA-mediated target gene suppression and cell transformation potential. Altogether, our findings of USP37-modulating PLZF/RARA stability and cell transformation suggest that USP37 is a potential therapeutic target for PLZF/RARA-associated APL.

Beez S, Demmer P, Puccetti E
Targeting the acute promyelocytic leukemia-associated fusion proteins PML/RARα and PLZF/RARα with interfering peptides.
PLoS One. 2012; 7(11):e48636 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
In acute promyelocytic leukemia (APL), hematopoietic differentiation is blocked and immature blasts accumulate in the bone marrow and blood. APL is associated with chromosomal aberrations, including t(15;17) and t(11;17). For these two translocations, the retinoic acid receptor alpha (RARα) is fused to the promyelocytic leukemia (PML) gene or the promyelocytic zinc finger (PLZF) gene, respectively. Both fusion proteins lead to the formation of a high-molecular-weight complex. High-molecular-weight complexes are caused by the "coiled-coil" domain of PML or the BTB/POZ domain of PLZF. PML/RARα without the "coiled-coil" fails to block differentiation and mediates an all-trans retinoic acid-response. Similarly, mutations in the BTB/POZ domain disrupt the high-molecular-weight complex, abolishing the leukemic potential of PLZF/RARα. Specific interfering polypeptides were used to target the oligomerization domain of PML/RARα or PLZF/RARα. PML/RARα and PLZF/RARα were analyzed for the ability to form high-molecular-weight complexes, the protein stability and the potential to induce a leukemic phenotype in the presence of the interfering peptides. Expression of these interfering peptides resulted in a reduced replating efficiency and overcame the differentiation block induced by PML/RARα and PLZF/RARα in murine hematopoietic stem cells. This expression also destabilized the PLZF/RARα-induced high-molecular-weight complex formation and caused the degradation of the fusion protein. Targeting fusion proteins through interfering peptides is a promising approach to further elucidate the biology of leukemia.

Geng Z, Zhang H, Wang D, et al.
Combination of cytogenetic analysis and molecular screening in patients with de novo acute myeloid leukemia.
J Huazhong Univ Sci Technolog Med Sci. 2012; 32(4):501-10 [PubMed] Related Publications
Nowadays the role of genetic findings in determining the diagnosis, therapy and prognosis of acute myeloid leukemia (AML) has become more valuable. To improve and validate the detection of clonal chromosomal aberrations in leukemia, we designed a combined application of karyotyping with multiplex reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH), and addressed the expression and distribution of fusion genes among the subtypes of Chinese adult patients with de novo AML. Multiplex RT-PCR assays were performed on 477 samples from newly diagnosed AML patients, and cytogenetic data were obtained from 373 of them by R or G banding techniques and those in some cases were confirmed by FISH. The PCR products in some suspected cases were tested by two-directional sequencing. The results showed that except unqualified samples, fusion genes were detected by multiplex RT-PCR in 211 of 474 patients (44.51%), including AML1-ETO, CBFβ-MYH11, PML-RARα, PLZF-RARα, NPM-RARα, MLL rearrangements, BCR-ABL, DEK-CAN, SET-CAN, TEL-PDGFR, TLS-ERG, AML1-MDS1 (EVI-1). In 373 patients, who took both multiplex RT-PCR and karyotype analysis, the detection rate of chromosomal aberrations by using multiplex RT-PCR and karyotyping was 160/373 (42.89%) and 179/373 (47.98%) respectively, and the combination could optimize the detection rate of clonal genetic abnormalities to 216/373 (57.90%). The PCR results from 11 cases "normal" in karyotyping but abnormal in RT-PCR for MLL rearrangements were confirmed by two-directional sequencing. It is concluded that karyotype studies remain the cornerstone for genetic testing; conventional cytogenetics and molecular-based methods are complementary tests for the detection of clonal genetic aberrations in AML, especially for the cryptic or submicroscopic aberrations. Once a genetic marker has been identified by combined analysis, it could be used to monitor residual disease during/after chemotherapy, by quantitative RT-PCR and/or FISH.

Wasim M, Mansha M, Kofler A, et al.
Promyelocytic leukemia zinc finger protein (PLZF) enhances glucocorticoid-induced apoptosis in leukemic cell line NALM6.
Pak J Pharm Sci. 2012; 25(3):617-21 [PubMed] Related Publications
Glucocorticoids (GC) actuate apoptosis as well as cell cycle arrest in lymphocytes, and included as core element in the lymphoid malignancy treatment. Despite clinical significance of GC and considerable efforts to understand it, the molecular basis of GC regulated cell death and the resistance phenomenon remains, however, poorly understood. Using Affymetrix-based whole genome expression profiling our group has previously identified a number of prominent glucocorticoid-response genes (Blood 107: 2061, 2006). Promyelocytic leukemia zinc finger (PLZF) was one of the best candidate genes. This study was proposed to investigate the possible role of PLZF in GC regulated cell death in leukemic model cell line NALM6. To this end, we generated NALM6 cell line (bulk) transduced with a retroviral expression vectors, pHR-SFFV-PLZF-IRES-Puro (U426) and pHR-SFFV-Venus-IRES-Puro (U417), as control, for constitutive gene-expression. HEK293T cells were transfected transiently to generate viral particles. These cell lines were characterized by Western blotting and used to assay the effect of constitutive PLZF expression. In conclusion, we report that bona fide transcription repressor PLZF, which turned out as prominent GC-regulated gene both in vivo and in vitro situations was found to enhance the GC-induced cell death (basal) in leukemic model cell line NALM6 after 48 and 72h time points.

Rohr SS, Pelloso LA, Borgo A, et al.
Acute promyelocytic leukemia associated with the PLZF-RARA fusion gene: two additional cases with clinical and laboratorial peculiar presentations.
Med Oncol. 2012; 29(4):2345-7 [PubMed] Related Publications
Acute promyelocytic leukemia (APL) is characterized by the presence of the t(15;17) and PML-RARa rearrangement, with good response to treatment with retinoids. However, few cases of variant APL involving alternative chromosomal aberrations have been reported, including t(11;17)(q23;q21) (Wells et al. in Nat Genet 17:109-113, 1; Arnould et al. in Hum Mol Genet 8:1741-1749, 2) t(5;17)(q35;q12-21), t(11;17)(q13;q21) (Grimwade et al in Blood 96:1297-1308, 3) and der(17) (Rego et al. in Blood (ASH Annual Meeting Abstracts)114:Abstract 6, 4), whereby RARa is fused to the PLZF, NPM, NuMA, and STAT5b genes, respectively, have been described. These cases are characterized by distinct morphology, clinical presentation, and in respect to PLZF, a lack of differentiation response to retinoids leading to the need of different approaches concerning diagnostic methods and therapeutics. This paper describes two cases of APL associated with the PLZF-RARA fusion gene enrolled in the IC-APL trial that is a non-randomized, multicenter study conducted in Brazil, Mexico, Chile and Uruguay with the aim to improve the treatment outcome of APL patients in developing countries. These cases, although rare, offer a challenge to its early recognition and proper conduction.

Rainer J, Lelong J, Bindreither D, et al.
Research resource: transcriptional response to glucocorticoids in childhood acute lymphoblastic leukemia.
Mol Endocrinol. 2012; 26(1):178-93 [PubMed] Related Publications
Glucocorticoids (GC) induce apoptosis in lymphoblasts and are thus essential in the treatment of acute lymphoblastic leukemia (ALL). Their effects result from gene regulations via the GC receptor (NR3C1/GR), but it is unknown how these changes evolve, what the primary GR targets are, and to what extent responses differ between ALL subtypes and nonlymphoid malignancies. We delineated the transcriptional response to GC on the exon level in a time-resolved manner in a precursor B- and a T childhood ALL model employing Exon microarrays and combined this with genome-wide NR3C1-binding site detection using chromatin immunoprecipitation-on-chip technology. This integrative approach showed that the response was strongly influenced by kinetics and extent of GR autoinduction in both models. Although remarkable differences between the ALL systems were apparent, we defined a set of common response genes enriched in apoptosis-related processes. Globally, GR binding was higher for GC-induced vs. -repressed genes, suggesting that GR mediates gene repression by interaction with distant enhancers or by cross talk with other transcription factors. Exon level analysis defined several new GC-regulated transcript variants of genes, including ATP4B, GPR98, TBCD, and ZBTB16. Our study provides unprecedented insight into the transcriptional response to GC in ALL cells, essential to understand this biologically and clinically important phenomenon. We found evidence of cell type-specific as well as common responses, possibly related to apoptosis induction, and detected induction of novel transcript variants by GC in the investigated systems. Finally, we implemented a bioinformatic framework that might be useful for high-density microarray analyses to identify alternative transcript variant expression.

Spicuglia S, Vincent-Fabert C, Benoukraf T, et al.
Characterisation of genome-wide PLZF/RARA target genes.
PLoS One. 2011; 6(9):e24176 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
The PLZF/RARA fusion protein generated by the t(11;17)(q23;q21) translocation in acute promyelocytic leukaemia (APL) is believed to act as an oncogenic transcriptional regulator recruiting epigenetic factors to genes important for its transforming potential. However, molecular mechanisms associated with PLZF/RARA-dependent leukaemogenesis still remain unclear.We searched for specific PLZF/RARA target genes by ChIP-on-chip in the haematopoietic cell line U937 conditionally expressing PLZF/RARA. By comparing bound regions found in U937 cells expressing endogenous PLZF with PLZF/RARA-induced U937 cells, we isolated specific PLZF/RARA target gene promoters. We next analysed gene expression profiles of our identified target genes in PLZF/RARA APL patients and analysed DNA sequences and epigenetic modification at PLZF/RARA binding sites. We identify 413 specific PLZF/RARA target genes including a number encoding transcription factors involved in the regulation of haematopoiesis. Among these genes, 22 were significantly down regulated in primary PLZF/RARA APL cells. In addition, repressed PLZF/RARA target genes were associated with increased levels of H3K27me3 and decreased levels of H3K9K14ac. Finally, sequence analysis of PLZF/RARA bound sequences reveals the presence of both consensus and degenerated RAREs as well as enrichment for tissue-specific transcription factor motifs, highlighting the complexity of targeting fusion protein to chromatin. Our study suggests that PLZF/RARA directly targets genes important for haematopoietic development and supports the notion that PLZF/RARA acts mainly as an epigenetic regulator of its direct target genes.

Steinert G, Oancea C, Roos J, et al.
Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARα and PLZF/RARα.
PLoS One. 2011; 6(7):e22540 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARα, PLZF/RARα, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARα and PLZF/RARα or AML-1/ETO activate Wnt signaling by upregulating γ-catenin and β-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARα-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings.

Tsou JH, Chang KC, Chang-Liao PY, et al.
Aberrantly expressed AURKC enhances the transformation and tumourigenicity of epithelial cells.
J Pathol. 2011; 225(2):243-54 [PubMed] Related Publications
Over-expression of AURKC has been detected in human colorectal cancers, thyroid carcinoma and several cancer cell lines. However, the regulation and clinical implications of over-expressed AURKC in cancer cells are unclear. Here we show that elevated AURKC increases the proliferation, transformation and migration of cancer cells. Importantly, the kinase activity of AURKC is required for these tumour-associated properties. Analysis of human cancer specimens shows that the expression of AURKC is increased in cervical cancer, and is highly correlated with staging in colorectal cancer. Over-expressed AURKC-GFP localizes to the centromeric regions of mitotic chromosomes and results in a decreased level of AURKB, a key regulator of spindle checkpoint. Expression of AURKC is down-regulated by PLZF, a transcriptional repressor, through recruitment to its promoter region. The expression levels of PLZF and AURKC mRNA display opposite patterns in human cervical and colorectal cancers. Taken together, our results provide important insights into human cancers with AURKC expression, which may serve as a potential target for cancer therapy in the future.

Huang Y, Hou JK, Chen TT, et al.
PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway.
Autophagy. 2011; 7(10):1132-44 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Autophagy is a highly conserved, closely regulated homeostatic cellular activity that allows for the bulk degradation of long-lived proteins and cytoplasmic organelles. Its roles in cancer initiation and progression and in determining the response of tumor cells to anticancer therapy are complicated, and only limited investigation has been conducted on the potential significance of autophagy in the pathogenesis and therapeutic response of acute myeloid leukemia. Here we demonstrate that the inducible or transfected expression of the acute promyelocytic leukemia (APL)-specific PML-RARα, but not PLZF-RARα or NPM-RARα, fusion protein upregulates constitutive autophagy activation in leukemic and nonleukemic cells, as evaluated by hallmarks for autophagy including transmission electron microscopy. The significant increase in autophagic activity is also found in the leukemic cells-infiltrated bone marrow and spleen from PML-RARα-transplanted leukemic mice. The autophagy inhibitor 3-methyladenine significantly abrogates the autophagic events upregulated by PML-RARα, while the autophagic flux assay reveals that the fusion protein induces autophagy by increasing the on-rate of autophagic sequestration. Furthermore, this modulation of autophagy by PML-RARα is possibly mediated by a decreased activation of the Akt/mTOR pathway. Finally, we also show that autophagy contributes to the anti-apoptotic function of the PML-RARα protein. Given the critical role of the PML-RARα oncoprotein in APL pathogenesis, this study suggests an important role of autophagy in the development and treatment of this disease.

Constantinides MG, Picard D, Savage AK, Bendelac A
A naive-like population of human CD1d-restricted T cells expressing intermediate levels of promyelocytic leukemia zinc finger.
J Immunol. 2011; 187(1):309-15 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Rare CD1d-α-galactosylceramide-specific T cells that do not express the invariant Vα24 chain of human NKT cells were recently identified after expansion in vitro with the lipid Ag, but their phenotype and frequency in vivo and lineage relationship with NKT cells could not be elucidated. By using a CD1d tetramer-based method to enrich these cells from fresh peripheral blood, we demonstrated their naive-like CD62L(high)CD45RO(-)CD4(+) phenotype and relatively high frequency of ∼10(-5) in several healthy individuals. Notably, these cells expressed the NKT lineage-specific transcription promyelocytic leukemia zinc finger (PLZF), indicating a developmental relationship with NKT cells and ruling out the possibility that they were conventional MHC-restricted T cells cross-reacting against CD1d-α-galactosylceramide. Although PLZF is known to direct the effector program of NKT cells, we show in this study that the naive-like cells expressed it at a significantly lower amount than NKT cells. Further, we present mouse studies demonstrating a sharp PLZF expression threshold requirement for induction of the effector phenotype. These findings directly demonstrate in vivo the existence of naive-like CD1d-restricted human T cells marked by intermediate levels of PLZF.

Martiniuk F, Damian DL, Thompson JF, et al.
TH17 is involved in the remarkable regression of metastatic malignant melanoma to topical diphencyprone.
J Drugs Dermatol. 2010; 9(11):1368-72 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
The authors provide an update on a previously reported patient with in-transit metastatic melanoma of the scalp treated with topical diphencyprone (DPCP). Molecular studies implicate the thymus-derived TH17 lymphocyte subset in a remarkable immunotherapeutic regression. The authors performed RT-PCR of total RNA from paraffin-embedded tissue before and after treatment with DPCP. Before treatment with DPCP, the authors found elevated expression of IL 17C/D/E/F; after treatment there was no detectable expression. Conversely, increased expression of PLZF/CD27 and CTLA4 was seen after treatment with no expression before treatment. No expression of IL17A/B, CD7, RORgTand FoxP3 were before or after treatment. Conclusions are limited to only the time samples were obtained. Remarkable regression of an in-transit metastatic melanoma treated with the immunomodulatory agent DPCP showed gain and loss of gene expression of the TH17 pathway. Further study of this pathway from NK to NK-T to TH7 and TH1 cells both with and without accessory or dendritic cells will improve understanding of contact sensitizers as topical immunomodulators.

Fréchette I, Darsigny M, Brochu-Gaudreau K, et al.
The Promyelocytic Leukemia Zinc Finger (PLZF ) gene is a novel transcriptional target of the CCAAT-Displacement-protein (CUX1) repressor.
FEBS J. 2010; 277(20):4241-53 [PubMed] Related Publications
The CCAAT-Displacement-Protein (CUX1) can transcriptionally repress sucrase–isomaltase gene expression, a specific product of enterocytes that becomes re-expressed during human colonic polyposis. Little is known of the gene repertoire that is directly affected by CUX1 in the intestinal epithelial context. This article identifies the Promyelocytic Leukemia Zinc Finger (PLZF) gene as a transcriptional target for the CUX1 repressor. CUX1 interacts in vivo with multiple DNA-binding sites in the 5′-UTR and promoter of the PLZF gene in colorectal cancer cells, a region that is functionally targeted by CUX1 in cotransfection assays. PLZF was found to be induced in colorectal cancer cell lines, correlating with a low detectable level of CUX1, a pattern that was reversed in normal human colonocytes. Reduction of p200CUX1 expression by RNAi in the Caco-2/15 cell line increased PLZF gene transcript expression. Because of the implication of Plzf in the regulation of stem cell maintenance, as well as Wnt and Ras signaling, in other systems, our observations suggest that the novel genetic relationship between CUX1 and PLZF could be of relevance to human diseases, such as leukemia, and open up a new field of investigation for the implication of these regulators during intestinal polyposis and cancer.

Pomerantz RG, Mirvish ED, Erdos G, et al.
Novel approach to gene expression profiling in Sézary syndrome.
Br J Dermatol. 2010; 163(5):1090-4 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
BACKGROUND: Microarray hybridization studies in Sézary syndrome (SS) have compared T lymphocytes from patients with cutaneous T-cell lymphoma with those of normal controls; a major limitation of this design is that significant inherent genetic variability of lymphocyte populations between individuals may produce differences in gene expression unrelated to disease state.
OBJECTIVE: The objective of this study was to minimize the heterogeneity of information derived from whole-genome expression analysis and to identify specific genetic differences between highly purified malignant and nonmalignant (control) T cells from the same patient with SS.
METHODS: Peripheral blood mononuclear cells were obtained from a patient with SS, stained with anti-T-cell receptor Vb (TCR-Vb) antibodies, and sorted by multiparameter flow cytometry. Malignant cells expressed the dominant TCR-Vb; control T cells lacked the dominant TCR-Vb but were otherwise phenotypically identical (CD3+CD4+CD45RO+). These cell populations were compared using the Illumina Inc. Sentrix Human-6 expression BeadChip system.
RESULTS: Transcriptome analysis using the J5 test, which was selected for data analysis based on an efficiency analysis of competing statistical methods, showed differential expression of 44 genes between the malignant and nonmalignant cell subsets. Promyelocytic leukaemia zinc finger protein (ZBTB16) was the most profoundly upregulated gene in the malignant cell population, while interferon regulatory factor 3 (IRF3) and interferon-induced protein 35 (IFI35), which are important elements of the cellular response to viral infection, were significantly downregulated.
CONCLUSIONS: The results of this study suggest the feasibility of this novel comparative approach to genomic profiling in SS. Using this method, we identified several differentially expressed genes and pathways not previously described in SS. While these findings require validation in larger studies, they may be important in SS pathogenesis.

Sirikanjanapong S, Lanson B, Amin M, et al.
Collision tumor of primary laryngeal mucosal melanoma and invasive squamous cell carcinoma with IL-17A and CD70 gene over-expression.
Head Neck Pathol. 2010; 4(4):295-9 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
The most common primary malignancy of the larynx is the squamous cell carcinoma (SCC). The primary malignant melanoma is quite rare in this location. Less than 60 cases of laryngeal melanomas have been reported to date. To our knowledge, collision primary malignant melanoma and invasive squamous cell carcinoma in the vocal cords has not been reported. We report a 53-year-old male patient who was diagnosed with a collision tumor of laryngeal melanoma and invasive SCC. Multiple Th17 pathway related genes including CTLA-4, IL-17A-F, PLZF, FoxP3, RorγT, CD27, and CD70 were analyzed by reverse transcriptase-polymerase chain reaction (Rt-PCR) in this case. Both IL-17A and CD70 genes were detected in this case of collision tumor. The results may define useful biomarkers for early diagnosis of mucosal melanoma and open an immunotherapeutic field for clinical management with the potential benefit from the immunomodulators that enhance both genes.

Shi J, Sun M, Vogt PK
Smooth muscle α-actin is a direct target of PLZF: effects on the cytoskeleton and on susceptibility to oncogenic transformation.
Oncotarget. 2010; 1(1):9-21 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Changes in cell morphology and rearrangements of the actin cytoskeleton are common features accompanying cell transformation induced by various oncogenes. In this study, we show that promyelocytic leukemia zinc finger protein (PLZF) binds to the promoter of smooth muscle α-actin, reducing mRNA and protein levels encoded by this gene and resulting in a reorganization of the actin cytoskeleton. In cultures of chicken embryo fibroblasts (CEF), this effect on α-actin expression is correlated with a change in cellular phenotype from spindle shaped to polygonal and flattened. This morphological change is dependent on Ras function. The polygonal, flattened CEF show a high degree of resistance to the transforming activity of several oncoproteins. Our results support the conclusion that reorganization of the actin cytoskeleton plays an important role in tumor suppression by PLZF.

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