DOCSLIB.ORG

Onc2010217.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Onc2010217.Pdf Oncogene (2010) 29, 4671–4681 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc ORIGINAL ARTICLE DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung T Shibata1,2, A Kokubu1, M Miyamoto1, F Hosoda1, M Gotoh2, K Tsuta3, H Asamura4, Y Matsuno5, T Kondo6, I Imoto7,8, J Inazawa7,8 and S Hirohashi1,2 1Cancer Genomics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; 2Pathology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; 3Clinical Laboratory Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan; 4Division of Thoracic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan; 5Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan; 6Proteome Bioinfomatics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; 7Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan and 8Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan Lung cancer shows diverse histological subtypes. Large- Introduction cell neuroendocrine cell carcinoma and small-cell lung carcinoma show similar histological features and clinical Lung cancer is one of the most prevalent cancers behaviors, and can be classified as high-grade neuro- worldwide, and shows diverse histological subtypes, endocrine carcinoma (HGNEC) of the lung. Here we including adenocarcinoma, squamous cell carcinoma, elucidated the molecular classification of pulmonary large-cell carcinoma, large-cell neuroendocrine carcino- endocrine tumors by copy-number profiling. We compared ma (LCNEC) and small-cell lung carcinoma (SCLC; alterations of copy number with the clinical outcome of Travis and Brambilla, 2004). The latter two share HGNEC and identified a chromosomal gain of the DEK common histological features such as neuroendocrine oncogene locus (6p22.3) that was significantly associated differentiation and belong to a spectrum of endocrine with poor prognosis. We further confirmed that DEK neoplasms of the lung, which include benign (typical overexpression was associated with poor prognosis in a carcinoid; TC), intermediately malignant (atypical larger set of HGNEC. Downregulation of DEK by small carcinoid; AC) and highly malignant (LCNEC and hairpin RNA led to a marked reduction of in vitro colony SCLC) tumors (Travis et al., 1991; Travis and Brambil- formation, in vivo tumorigenicity and chemo-resistance, la, 2004). LCNEC and SCLC show similar clinical and was associated with loss of lung cancer stem cell behavior and can be classified as high-grade neuro- markers. Gene expression profiling revealed that DEK endocrine carcinoma (HGNEC; Asamura et al., 2006). downregulation was associated with altered expression of Genome-wide expression profiling has supported this transcriptional regulators, which specifically include classification, and led to the division of HGNEC into known targets of interchromosomal translocations in groups showing better and poor prognosis, showing no hematopoietic tumors, and knockdown of these epigenetic correlation with histological subtype (LCNEC or SCLC; modifiers affected colony formation activity. Our study Jones et al., 2004). However, details of the molecular showed that DEK overexpression, partly through an alterations in HGNEC, especially those associated with increase in its gene dose, mediates the activity of global malignant phenotypes, remain largely unknown. transcriptional regulators and is associated with tumor Recently, many studies have reported that a self- initiation activity and poor prognosis in HGNEC. renewing population of cancer cells, known as cancer Oncogene (2010) 29, 4671–4681; doi:10.1038/onc.2010.217; stem cell (CSC) or tumor-initiating cell, is responsible published online 14 June 2010 for histological heterogeneity, tumor recurrence, organ metastasis and drug resistance, which are hallmarks of Keywords: lung cancer; cancer stem cell; DEK; malignancy and related to poor prognosis (Visvader and neuroendocrine Lindeman, 2008). Interestingly, HGNEC is well known to frequently coexist with other histological subtypes such as adenocarcinoma or squamous cell carcinoma (so-called combined tumor; Travis and Brambilla, 2004), suggesting that this tumor contains a pluripotent stem cell-like population. Although several putative markers for lung cancer stem cells (such as CD133 and Correspondence: Dr T Shibata, Cancer Genomics Project, National ALDH1A) have been proposed (Peacock and Watkins, Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 2008), the molecular mechanisms responsible for main- 104-0045, Japan, E-mail: [email protected] taining these stem cell features are largely unknown. Received 29 September 2009; revised 26 April 2010; accepted 2 May To further understand the molecular mechanisms 2010; published online 14 June 2010 related to the progression of HGNEC, we have DEK oncoprotein in pulmonary endocrine carcinoma T Shibata et al 4672 compared copy-number alterations with clinical out- Thus, the copy number-based classification elucidated a come of HGNEC and shown that chromosomal gain of carcinoid subgroup, which contains all carcinoid sam- the DEK gene locus is significantly associated with poor ples and exceptionally one LCNEC case (Carcinoid prognosis. DEK was originally identified as a fusion branch in Figure 1b). Unsupervised classification partner of t(6;9)(p23;q34) translocation in a subtype of revealed three subclasses (HGNEC-BR1-3) in the acute myeloid leukemia; von Lindern et al., 1992) and is HGNEC group, suggesting of the possibility of mole- overexpressed in several types of solid tumor such as cular subtypes in HGNEC, and SCLC was significantly liver cancer (Kondoh et al., 1999; Carro et al., 2006; segregated in HGNEC-BR1 (P ¼ 0.00246). We then Khodadoust et al.,2009). performed extensive molecular characterization of the lung endocrine tumors by the immunohistochemical analysis of candidate tumor suppressor (p53, PTEN and Results RB) and oncogene (SKP2, EGFR, MET and KIT) products in this cohort (Figure 1b). Aberrant expres- Molecular classification of endocrine tumors of the lung sions of these proteins were more frequent in HGNEC, To clarify the chromosomal alteration profile of the but no significant correlation was observed among endocrine tumors of the lung, we performed array-based HGNEC-branches and oncoprotein expressions (data comparative genomic hybridization (CGH) analysis of not shown). Notwithstanding the inability to character- the 49 primary tumors (11 cases of TC, 2 cases of AC, 8 ize this classification by known molecular markers, cases of SCLC and 28 cases of LCNEC), which include when clinical outcome was compared, patients in samples analyzed in our previous report (Peng et al., HGNEC-BR2 showed a significantly better outcome 2005). We then conducted unsupervised cluster analysis than the others (HGNEC-BR1/3; Figure 1c and of the CGH data to examine whether histological Supplementary Figure 1), suggesting of novel molecular subtypes have any association with genomic classifica- markers that can discriminate the two groups. Then we tion (Figure 1a). As shown in Figures 1a and b, searched for the genetic differences between HGNEC- chromosome alterations in TC and AC are characteristic BR1/3 (poor prognosis) and HGNEC-BR2 (good and clearly distinct from those observed in HGNEC prognosis) and found that copy number alterations at (LCNEC and SCLC; distinctive bacterial artificial four loci (12q13 EPS8 (adjusted P ¼ 0.0033), 6p22.3 chromosome (BAC) clones between carcinoid and DEK (P ¼ 0.017), 2p24 NBAS (P ¼ 0.022) and 2q31.3 HGNEC are listed in the Supplementary Table 1). ITGA4 (P ¼ 0.046)) differed significantly between the Figure 1 Molecular classification of pulmonary endocrine tumors. (a) Hierarchical cluster analysis of pulmonary endocrine tumors based on the changes in copy number at 800 loci. Red indicates copy number gain/amplification and green indicates copy number loss. Color bars at the bottom show subgroups. (b) Association between immunohistological features and genetic classification in pulmonary endocrine tumors. Each column indicates a single primary tumor. In the histology row, blue, yellow, red and green boxes indicate TC, AC, LCNEC and SCLC, respectively. In the p53 row, solid and gray boxes indicate strong and moderate p53 protein expression, respectively, which are suggestive of mutant p53. In the PTEN and RB rows, solid box indicates loss of tumor-suppressor protein expression. In other rows, solid and gray boxes indicate strong and moderate oncoprotein expression, respectively. (c) Genetic classification of HGNEC is associated with clinical outcome by Kaplan–Meier analysis. (d) Significant difference in copy number of the DEK gene locus between HGNEC-BR1/3 and HGNEC-BR2. Oncogene DEK oncoprotein in pulmonary endocrine carcinoma T Shibata et al 4673 two groups. In this study, we focused on the DEK gene DEK expression such as that around small vessels, because it encodes a well-known leukemia oncoprotein. which has been suggested to represent a CSC niche in Analysis of other targets (EPS8 encoding an epidermal neural tumors (Calabrese et al., 2007), or a scattered growth factor receptor pathway substrate, and NBAS pattern within the
Load more

Recommended publications
  • Fish and Shellfish Immunology 95 (2019) 538–545
    Fish and Shellfish Immunology 95 (2019) 538–545 Contents lists available at ScienceDirect Fish and Shellfish Immunology journal homepage: www.elsevier.com/locate/fsi Full length article Congenital asplenia due to a tlx1 mutation reduces resistance to Aeromonas T hydrophila infection in zebrafish ∗ Lang Xiea,b, Yixi Taoa,b, Ronghua Wua,b, Qin Yec, Hao Xua,b, Yun Lia,b, a Institute of Three Gorges Ecological Fisheries of Chongqing, College of Animal Science and Technology, Southwest University, Chongqing, 400715, China b Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, Southwest University, Chongqing, 400715, China c School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China ARTICLE INFO ABSTRACT Keywords: It is documented that tlx1, an orphan homeobox gene, plays critical roles in the regulation of early spleen tlx1 knock-out developmental in mammalian species. However, there is no direct evidence supporting the functions of tlx1 in Congenital asplenia non-mammalian species, especially in fish. In this study, we demonstrated that tlx1 is expressed in the splenic Aeromonas hydrophila primordia as early as 52 hours post-fertilization (hpf) in zebrafish. A tlx1−/− homozygous mutant line was Disease resistance generated via CRISPR/Cas9 to elucidate the roles of tlx1 in spleen development in zebrafish. In the tlx1−/− background, tlx1−/− cells persisted in the splenic primordia until 52 hpf but were no longer detectable after 53 hpf, suggesting perturbation of early spleen development. The zebrafish also exhibited congenital asplenia caused by the tlx1 mutation. Asplenic zebrafish can survive and breed normally under standard laboratory conditions, but the survival rate of animals infected with Aeromonas hydrophila was significantly lower than that of wild-type (WT) zebrafish.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Supplemental Materials ZNF281 Enhances Cardiac Reprogramming
    Supplemental Materials ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby and Eric N. Olson Supplemental Table 1; related to Figure 1. Supplemental Table 2; related to Figure 1. Supplemental Table 3; related to the “quantitative mRNA measurement” in Materials and Methods section. Supplemental Table 4; related to the “ChIP-seq, gene ontology and pathway analysis” and “RNA-seq” and gene ontology analysis” in Materials and Methods section. Supplemental Figure S1; related to Figure 1. Supplemental Figure S2; related to Figure 2. Supplemental Figure S3; related to Figure 3. Supplemental Figure S4; related to Figure 4. Supplemental Figure S5; related to Figure 6. Supplemental Table S1. Genes included in human retroviral ORF cDNA library. Gene Gene Gene Gene Gene Gene Gene Gene Symbol Symbol Symbol Symbol Symbol Symbol Symbol Symbol AATF BMP8A CEBPE CTNNB1 ESR2 GDF3 HOXA5 IL17D ADIPOQ BRPF1 CEBPG CUX1 ESRRA GDF6 HOXA6 IL17F ADNP BRPF3 CERS1 CX3CL1 ETS1 GIN1 HOXA7 IL18 AEBP1 BUD31 CERS2 CXCL10 ETS2 GLIS3 HOXB1 IL19 AFF4 C17ORF77 CERS4 CXCL11 ETV3 GMEB1 HOXB13 IL1A AHR C1QTNF4 CFL2 CXCL12 ETV7 GPBP1 HOXB5 IL1B AIMP1 C21ORF66 CHIA CXCL13 FAM3B GPER HOXB6 IL1F3 ALS2CR8 CBFA2T2 CIR1 CXCL14 FAM3D GPI HOXB7 IL1F5 ALX1 CBFA2T3 CITED1 CXCL16 FASLG GREM1 HOXB9 IL1F6 ARGFX CBFB CITED2 CXCL3 FBLN1 GREM2 HOXC4 IL1F7
    [Show full text]
  • High-Resolution Analysis of Chromosomal Breakpoints and Genomic Instability Identifies PTPRD As a Candidate Tumor Suppressor Gene in Neuroblastoma
    Research Article High-Resolution Analysis of Chromosomal Breakpoints and Genomic Instability Identifies PTPRD as a Candidate Tumor Suppressor Gene in Neuroblastoma Raymond L. Stallings,1 Prakash Nair,1 John M. Maris,2 Daniel Catchpoole,3 Michael McDermott,4 Anne O’Meara,5 and Fin Breatnach5 1Children’s Cancer Research Institute and Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas; 2Division of Oncology, Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 3The Tumor Bank, Children’s Hospital at Westmead, Sydney, New South Wales, Australia; and Departments of 4Pathology and 5Oncology, Our Lady’s Hospital for Sick Children, Dublin, Ireland Abstract and death from disease. Patient age, tumor stage, and several Although neuroblastoma is characterized by numerous different genetic abnormalities are important factors that influence clinical outcome. Loss of 1p and 11q, gain of 17q, and amplification recurrent, large-scale chromosomal imbalances, the genes MYCN targeted by such imbalances have remained elusive. We have of the oncogene are particularly strong genetic indicators of poor disease outcome (2–5). Two of these abnormalities, loss of 11q applied whole-genome oligonucleotide array comparative MYCN genomic hybridization (median probe spacing 6 kb) to 56 and amplification, form the basis for dividing advanced- stage neuroblastomas into genetic subtypes due to their rather neuroblastoma tumors and cell lines to identify genes involved with disease pathogenesis. This set oftumors was selected for striking inverse distribution in tumors (6, 7). Many other recurrent having either 11q loss or MYCN amplification, abnormalities partial chromosomal imbalances, including loss of 3p, 4p, 9p, and that define the two most common genetic subtypes of 14q and gain of 1q, 2p, 7q, and 11p, have been identified by metastatic neuroblastoma.
    [Show full text]
  • SUPPLEMENTARY MATERIAL Bone Morphogenetic Protein 4 Promotes
    www.intjdevbiol.com doi: 10.1387/ijdb.160040mk SUPPLEMENTARY MATERIAL corresponding to: Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells SUMIYO MIMURA, MIKA SUGA, KAORI OKADA, MASAKI KINEHARA, HIROKI NIKAWA and MIHO K. FURUE* *Address correspondence to: Miho Kusuda Furue. Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. Tel: 81-72-641-9819. Fax: 81-72-641-9812. E-mail: [email protected] Full text for this paper is available at: http://dx.doi.org/10.1387/ijdb.160040mk TABLE S1 PRIMER LIST FOR QRT-PCR Gene forward reverse AP2α AATTTCTCAACCGACAACATT ATCTGTTTTGTAGCCAGGAGC CDX2 CTGGAGCTGGAGAAGGAGTTTC ATTTTAACCTGCCTCTCAGAGAGC DLX1 AGTTTGCAGTTGCAGGCTTT CCCTGCTTCATCAGCTTCTT FOXD3 CAGCGGTTCGGCGGGAGG TGAGTGAGAGGTTGTGGCGGATG GAPDH CAAAGTTGTCATGGATGACC CCATGGAGAAGGCTGGGG MSX1 GGATCAGACTTCGGAGAGTGAACT GCCTTCCCTTTAACCCTCACA NANOG TGAACCTCAGCTACAAACAG TGGTGGTAGGAAGAGTAAAG OCT4 GACAGGGGGAGGGGAGGAGCTAGG CTTCCCTCCAACCAGTTGCCCCAAA PAX3 TTGCAATGGCCTCTCAC AGGGGAGAGCGCGTAATC PAX6 GTCCATCTTTGCTTGGGAAA TAGCCAGGTTGCGAAGAACT p75 TCATCCCTGTCTATTGCTCCA TGTTCTGCTTGCAGCTGTTC SOX9 AATGGAGCAGCGAAATCAAC CAGAGAGATTTAGCACACTGATC SOX10 GACCAGTACCCGCACCTG CGCTTGTCACTTTCGTTCAG Suppl. Fig. S1. Comparison of the gene expression profiles of the ES cells and the cells induced by NC and NC-B condition. Scatter plots compares the normalized expression of every gene on the array (refer to Table S3). The central line
    [Show full text]
  • 1714 Gene Comprehensive Cancer Panel Enriched for Clinically Actionable Genes with Additional Biologically Relevant Genes 400-500X Average Coverage on Tumor
    xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A
    [Show full text]
  • Novel and Highly Recurrent Chromosomal Alterations in Se´Zary Syndrome
    Research Article Novel and Highly Recurrent Chromosomal Alterations in Se´zary Syndrome Maarten H. Vermeer,1 Remco van Doorn,1 Remco Dijkman,1 Xin Mao,3 Sean Whittaker,3 Pieter C. van Voorst Vader,4 Marie-Jeanne P. Gerritsen,5 Marie-Louise Geerts,6 Sylke Gellrich,7 Ola So¨derberg,8 Karl-Johan Leuchowius,8 Ulf Landegren,8 Jacoba J. Out-Luiting,1 Jeroen Knijnenburg,2 Marije IJszenga,2 Karoly Szuhai,2 Rein Willemze,1 and Cornelis P. Tensen1 Departments of 1Dermatology and 2Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Dermatology, St Thomas’ Hospital, King’s College, London, United Kingdom; 4Department of Dermatology, University Medical Center Groningen, Groningen, the Netherlands; 5Department of Dermatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; 6Department of Dermatology, Gent University Hospital, Gent, Belgium; 7Department of Dermatology, Charite, Berlin, Germany; and 8Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden Abstract Introduction This study was designed to identify highly recurrent genetic Se´zary syndrome (Sz) is an aggressive type of cutaneous T-cell alterations typical of Se´zary syndrome (Sz), an aggressive lymphoma/leukemia of skin-homing, CD4+ memory T cells and is cutaneous T-cell lymphoma/leukemia, possibly revealing characterized by erythroderma, generalized lymphadenopathy, and pathogenetic mechanisms and novel therapeutic targets. the presence of neoplastic T cells (Se´zary cells) in the skin, lymph High-resolution array-based comparative genomic hybridiza- nodes, and peripheral blood (1). Sz has a poor prognosis, with a tion was done on malignant T cells from 20 patients. disease-specific 5-year survival of f24% (1).
    [Show full text]
  • Identification of Novel Mouse Delta1 Target Genes: Combination of Transcriptomics and Proteomics
    Institut für Experimentelle Genetik GSF – Forschungszentrum für Umwelt und Gesundheit Identification of novel mouse Delta1 target genes: Combination of transcriptomics and proteomics Christine Hutterer Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. A. Gierl Prüfer der Dissertation: 1. apl. Prof. Dr. J. Adamski 2. Univ.-Prof. Dr. W. Wurst Die Dissertation wurde am 31.01.2005 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 13.05.2005 angenommen. DANKSAGUNG Besonderer Dank gebührt Prof. Dr. Martin Hrabé de Angelis, Leiter des Instituts für experimentelle Genetik. Unter anderem durch seine Leidenschaft für die Wissenschaft wollte ich am IEG arbeiten. Ich möchte mich jedoch nicht nur für die wissenschaftlichen Ratschläge und Diskussionen bedanken, sondern auch für viele interessante nicht-wissenschaftliche Gespräche. Ebenfalls besonders bedanke ich mich bei meinem Doktorvater Dr. Jurek Adamski, dessen fachliche Meinung und positive Einstellung mich sehr motivierte. Großen Dank möchte ich der gesamten „Beckers-Arbeitsgruppe“ aussprechen. Allen voran Dr. Johannes Beckers, Leiter der Genregulation und Expression Profiling Arbeitsgruppe, für die Überlassung des Themas und die Betreuung meiner Doktorarbeit, die mir viel Entscheidungsfreiraum ließ, sowie für zahlreiche gute Ideen und lehrreiche Gespräche. Bei Tomek Mijalski möchte ich mich für seine stetige Hilfsbereitschaft und die entstandene Freundschaft besonders bedanken. Weiterhin bedanke ich mich ganz herzlich bei Dr. Sonja Becker für wertvolle Labortricks und Kniffe, die Durchsicht des Manuskripts und ihre herzliche Art. Vielen Dank an dieser Stelle auch an Kathrin Seidel für die gute technische Unterstützung im Labor und mit der Mausarbeit.
    [Show full text]
  • Genome-Wide Analysis Identifies Rag1 and Rag2 As Novel Notch1
    fcell-09-703338 July 7, 2021 Time: 18:5 # 1 ORIGINAL RESEARCH published: 12 July 2021 doi: 10.3389/fcell.2021.703338 Genome-Wide Analysis Identifies Rag1 and Rag2 as Novel Notch1 Transcriptional Targets in Thymocytes Yang Dong1,2†, Hao Guo1,2†, Donghai Wang2, Rongfu Tu2, Guoliang Qing2* and Hudan Liu1,2* 1 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China, 2 Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China Recombination activating genes 1 (Rag1) and Rag2 are expressed in immature lymphocytes and essential for generating the vast repertoire of antigen receptors. Yet, the mechanisms governing the transcription of Rag1 and Rag2 remain to be Edited by: Binghui Li, fully determined, particularly in thymocytes. Combining cDNA microarray and ChIP- Capital Medical University, China seq analysis, we identify Rag1 and Rag2 as novel Notch1 transcriptional targets in Reviewed by: acute T-cell lymphoblastic leukemia (T-ALL) cells. We further demonstrate that Notch1 Bo Li, Sun Yat-sen University, China transcriptional complexes directly bind the Rag1 and Rag2 locus in not only T-ALL Peng Li, but also primary double negative (DN) T-cell progenitors. Specifically, dimeric Notch1 Guangzhou Institutes of Biomedicine transcriptional complexes activate Rag1 and Rag2 through a novel cis-element bearing and Health, Chinese Academy of Sciences (CAS), China a sequence-paired site (SPS). In T-ALL and DN cells, dimerization-defective Notch1 *Correspondence: causes compromised Rag1 and Rag2 expression; conversely, dimerization-competent Guoliang Qing Notch1 achieves optimal upregulation of both. Collectively, these results reveal Notch1 [email protected] Hudan Liu dimerization-mediated transcription as one of the mechanisms for activating Rag1 and [email protected] Rag2 expression in both primary and transformed thymocytes.
    [Show full text]
  • (DN2MT) Progenitor Is a Target Cell for Leukemic Transformation by The
    Zweier-Renn et al., J Bone Marrow Res 2013, 1:1 Journal of Bone Marrow Research http://dx.doi.org/10.4172/jbmr.1000105 Research Article Open Access The DN2 Myeloid-T (DN2MT) Progenitor is a Target Cell for Leukemic Transformation by the TLX1 Oncogene Lynnsey A Zweier-Renn1,2, Irene Riz1, Teresa S Hawley3 and Robert G Hawley1,4* 1Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC, USA 2Graduate Program in Biochemistry and Molecular Genetics, George Washington University, Washington, DC, USA 3Flow Cytometry Core Facility, George Washington University, Washington, DC, USA 4Sino-US Joint Laboratory of Translational Medicine, Jining Medical University Affiliated Hospital, Jining Medical University, Jining, Shandong, China Abstract Introduction: Inappropriate activation of the TLX1 (T-cell leukemia homeobox 1) gene by chromosomal translocation is a recurrent event in human T-cell Acute Lymphoblastic Leukemia (T-ALL). Ectopic expression of TLX1 in murine bone marrow progenitor cells using a conventional retroviral vector efficiently yields immortalized cell lines and induces T-ALL-like tumors in mice after long latency. Methods: To eliminate a potential contribution of retroviral insertional mutagenesis to TLX1 immortalizing and transforming function, we incorporated the TLX1 gene into an insulated self-inactivating retroviral vector. Results: Retrovirally transduced TLX1-expressing murine bone marrow progenitor cells had a growth/survival advantage and readily gave rise to immortalized cell lines. Extensive characterization of 15 newly established cell lines failed to reveal a common retroviral integration site. This comprehensive analysis greatly extends our previous study involving a limited number of cell lines, providing additional support for the view that constitutive TLX1 expression is sufficient to initiate the series of events culminating in hematopoietic progenitor cell immortalization.
    [Show full text]
  • What Your Genome Doesn't Tell
    UC San Diego UC San Diego Electronic Theses and Dissertations Title Multi-layered epigenetic control of T cell fate decisions Permalink https://escholarship.org/uc/item/8rs7c7b3 Author Yu, Bingfei Publication Date 2018 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA SAN DIEGO Multi-layered epigenetic control of T cell fate decisions A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biology by Bingfei Yu Committee in charge: Professor Ananda Goldrath, Chair Professor John Chang Professor Stephen Hedrick Professor Cornelis Murre Professor Wei Wang 2018 Copyright Bingfei Yu, 2018 All rights reserved. The dissertation of Bingfei Yu is approved, and it is ac- ceptable in quality and form for publication on microfilm and electronically: Chair University of California San Diego 2018 iii DEDICATION To my parents who have been giving me countless love, trust and support to make me who I am. iv EPIGRAPH Stay hungary. Stay foolish. | Steve Jobs quoted from the back cover of the 1974 edition of the Whole Earth Catalog v TABLE OF CONTENTS Signature Page.................................. iii Dedication..................................... iv Epigraph.....................................v Table of Contents................................. vi List of Figures.................................. ix Acknowledgements................................x Vita........................................ xii Abstract of
    [Show full text]
  • Prdm13 Mediates the Balance of Inhibitory and Excitatory Neurons in Somatosensory Circuits
    Developmental Cell Article Prdm13 Mediates the Balance of Inhibitory and Excitatory Neurons in Somatosensory Circuits Joshua C. Chang,1 David M. Meredith,1 Paul R. Mayer,1 Mark D. Borromeo,1 Helen C. Lai,1 Yi-Hung Ou,2 and Jane E. Johnson1,* 1Department of Neuroscience 2Department of Cell Biology UT Southwestern Medical Center, Dallas, TX 75390, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2013.02.015 SUMMARY genesis to generate the correct composition of neurons is critical. Here, we identify a key component of the transcriptional Generating a balanced network of inhibitory and machinery that controls how neurons in the somatosensory cir- excitatory neurons during development requires pre- cuit are generated and how regulated specification of these cise transcriptional control. In the dorsal spinal cord, neurons leads to a correct excitatory/inhibitory balance during Ptf1a, a basic helix-loop-helix (bHLH) transcription development. activator, maintains this delicate balance by inducing Excitatory and inhibitory neurons in the spinal cord arise from homeodomain (HD) transcription factors such as progenitor populations within the ventricular zone of the dorsal neural tube (Gross et al., 2002; Mu¨ ller et al., 2002). These pro- Pax2 to specify the inhibitory lineage while suppress- genitors are competent to give rise to neurons in either class ing HD factors such as Tlx1/3 that specify the excit- depending on the basic helix-loop-helix (bHLH) transcription fac- atory lineage. We uncover the mechanism by which tors that are expressed (Helms and Johnson, 2003; Zhuang and Ptf1a represses excitatory cell fate in the inhibitory Sockanathan, 2006).
    [Show full text]