title: Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines.
abstract: Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2-10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings highlight biallelic deletions as a major class of chromosomal lesion in PMBL cell lines, while endorsing the latter as preclinical models for hunting and testing new biomarkers and actionable targets.
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.|Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Dai
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrentraut
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Eberth
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pommerenke
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Wilhelm G
authors.initials: WG
authors.lastname: Dirks
authors.affiliation: Department of Genome Analysis, HZI, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: University of Florida, Gainesville, FL, United States of America.
authors.forename: Srilaxmi
authors.initials: S
authors.lastname: Kalavalapalli
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Kaufmann
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Corrina
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Faehnrich
authors.affiliation: Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: MacLeod
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D020732:Cytogenetic Analysis; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008479:Mediastinal Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D032681:Spectral Karyotyping; D014158:Transcription, Genetic