42 results on '"Weniger MA"'
Search Results
2. Frequent gains of REL and BCL11A in mediastinal B-cell lymphoma selectively provoke up-regulated RNA and protein expression
- Author
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Weniger, MA, Pulford, K, Gesk, S, Ehrlich, S, Banham, AH, Lyne, L, Martin-Subero, JI, Siebert, R, Dyer, MJS, Moeller, P, and Barth, TFE
- Published
- 2016
3. Transcriptional profiling suggests that secondary and primary large B‐cell lymphomas of the gastrointestinal (GI) tract are blastic variants of GI marginal zone lymphoma
- Author
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Barth, TFE, primary, Barth, CA, additional, Kestler, HA, additional, Michl, P, additional, Weniger, MA, additional, Buchholz, M, additional, Möller, P, additional, and Gress, T, additional
- Published
- 2006
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4. Transcriptional profiling suggests that secondary and primary large B-cell lymphomas of the gastrointestinal (GI) tract are blastic variants of GI marginal zone lymphoma.
- Author
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Barth, TFE, Barth, CA, Kestler, HA, Michl, P, Weniger, MA, Buchholz, M, Möller, P, and Gress, T
- Abstract
The pathogenetic relationship of marginal zone B-cell lymphoma (MALT lymphoma) of the gastrointestinal (GI) tract and eventually co-existing aggressive B-cell lymphoma and primary aggressive B-cell lymphoma remains to be elucidated. The RNA of laser-microdissected cells was isolated and amplified from small and/or large cell compartments of eight MALT lymphomas (small cell lymphoma, SCL), 14 GI diffuse large B-cell lymphomas (large cell lymphoma, LCL), and ten GI B-cell lymphomas with composite small and large cell compartments (ComL) and expression analyses were performed using cDNA arrays. Hierarchical cluster analysis clearly separated SCL and LCL and the small and large cell compartments of ComL. Likewise, cluster analysis with all samples of SCL, LCL, and ComL yielded two main 'small cell' and 'large cell' branches. Furthermore, 60 genes were differentially expressed between SCL and LCL, and 82 genes between the small and large cell components of ComL; 26 genes were discriminators in both settings. Use of the profiles of ComL as training sets for class prediction resulted in 95% accuracy for the classification of SCL and LCL. Collectively, the data strongly suggest that both secondary and primary aggressive B-cell lymphomas of the GI tract are blastic marginal zone lymphomas. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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5. Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis
- Author
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Müller-Hermelink Hans K, Rosenwald Andreas, Schultz Jörg, Weniger Markus, Pinkert Stefan, Engelmann Julia C, Blenk Steffen, Müller Tobias, and Dandekar Thomas
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Mantle cell lymphoma (MCL) is an incurable B cell lymphoma and accounts for 6% of all non-Hodgkin's lymphomas. On the genetic level, MCL is characterized by the hallmark translocation t(11;14) that is present in most cases with few exceptions. Both gene expression and comparative genomic hybridization (CGH) data vary considerably between patients with implications for their prognosis. Methods We compare patients over and below the median of survival. Exploratory principal component analysis of gene expression data showed that the second principal component correlates well with patient survival. Explorative analysis of CGH data shows the same correlation. Results On chromosome 7 and 9 specific genes and bands are delineated which improve prognosis prediction independent of the previously described proliferation signature. We identify a compact survival predictor of seven genes for MCL patients. After extensive re-annotation using GEPAT, we established protein networks correlating with prognosis. Well known genes (CDC2, CCND1) and further proliferation markers (WEE1, CDC25, aurora kinases, BUB1, PCNA, E2F1) form a tight interaction network, but also non-proliferative genes (SOCS1, TUBA1B CEBPB) are shown to be associated with prognosis. Furthermore we show that aggressive MCL implicates a gene network shift to higher expressed genes in late cell cycle states and refine the set of non-proliferative genes implicated with bad prognosis in MCL. Conclusion The results from explorative data analysis of gene expression and CGH data are complementary to each other. Including further tests such as Wilcoxon rank test we point both to proliferative and non-proliferative gene networks implicated in inferior prognosis of MCL and identify suitable markers both in gene expression and CGH data.
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- 2008
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6. Genome Expression Pathway Analysis Tool – Analysis and visualization of microarray gene expression data under genomic, proteomic and metabolic context
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Engelmann Julia C, Weniger Markus, and Schultz Jörg
- Subjects
Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Regulation of gene expression is relevant to many areas of biology and medicine, in the study of treatments, diseases, and developmental stages. Microarrays can be used to measure the expression level of thousands of mRNAs at the same time, allowing insight into or comparison of different cellular conditions. The data derived out of microarray experiments is highly dimensional and often noisy, and interpretation of the results can get intricate. Although programs for the statistical analysis of microarray data exist, most of them lack an integration of analysis results and biological interpretation. Results We have developed GEPAT, Genome Expression Pathway Analysis Tool, offering an analysis of gene expression data under genomic, proteomic and metabolic context. We provide an integration of statistical methods for data import and data analysis together with a biological interpretation for subsets of probes or single probes on the chip. GEPAT imports various types of oligonucleotide and cDNA array data formats. Different normalization methods can be applied to the data, afterwards data annotation is performed. After import, GEPAT offers various statistical data analysis methods, as hierarchical, k-means and PCA clustering, a linear model based t-test or chromosomal profile comparison. The results of the analysis can be interpreted by enrichment of biological terms, pathway analysis or interaction networks. Different biological databases are included, to give various information for each probe on the chip. GEPAT offers no linear work flow, but allows the usage of any subset of probes and samples as a start for a new data analysis. GEPAT relies on established data analysis packages, offers a modular approach for an easy extension, and can be run on a computer grid to allow a large number of users. It is freely available under the LGPL open source license for academic and commercial users at http://gepat.sourceforge.net. Conclusion GEPAT is a modular, scalable and professional-grade software integrating analysis and interpretation of microarray gene expression data. An installation available for academic users can be found at http://gepat.bioapps.biozentrum.uni-wuerzburg.de.
- Published
- 2007
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7. An atlas of cells in the human tonsil.
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Massoni-Badosa R, Aguilar-Fernández S, Nieto JC, Soler-Vila P, Elosua-Bayes M, Marchese D, Kulis M, Vilas-Zornoza A, Bühler MM, Rashmi S, Alsinet C, Caratù G, Moutinho C, Ruiz S, Lorden P, Lunazzi G, Colomer D, Frigola G, Blevins W, Romero-Rivero L, Jiménez-Martínez V, Vidal A, Mateos-Jaimez J, Maiques-Diaz A, Ovejero S, Moreaux J, Palomino S, Gomez-Cabrero D, Agirre X, Weniger MA, King HW, Garner LC, Marini F, Cervera-Paz FJ, Baptista PM, Vilaseca I, Rosales C, Ruiz-Gaspà S, Talks B, Sidhpura K, Pascual-Reguant A, Hauser AE, Haniffa M, Prosper F, Küppers R, Gut IG, Campo E, Martin-Subero JI, and Heyn H
- Subjects
- Humans, Adult, Palatine Tonsil, B-Lymphocytes metabolism
- Abstract
Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil., Competing Interests: Declaration of interests H.H. is co-founder of Omniscope, SAB member of Nanostring and MiRXES, and consultant to Moderna and Singularity. J.C.N. is consultant to Omniscope., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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8. Transcriptional reprogramming by mutated IRF4 in lymphoma.
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Schleussner N, Cauchy P, Franke V, Giefing M, Fornes O, Vankadari N, Assi SA, Costanza M, Weniger MA, Akalin A, Anagnostopoulos I, Bukur T, Casarotto MG, Damm F, Daumke O, Edginton-White B, Gebhardt JCM, Grau M, Grunwald S, Hansmann ML, Hartmann S, Huber L, Kärgel E, Lusatis S, Noerenberg D, Obier N, Pannicke U, Fischer A, Reisser A, Rosenwald A, Schwarz K, Sundararaj S, Weilemann A, Winkler W, Xu W, Lenz G, Rajewsky K, Wasserman WW, Cockerill PN, Scheidereit C, Siebert R, Küppers R, Grosschedl R, Janz M, Bonifer C, and Mathas S
- Subjects
- Humans, B-Lymphocytes metabolism, DNA, Gene Expression Regulation, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Lymphoma genetics
- Abstract
Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF., (© 2023. The Author(s).)
- Published
- 2023
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9. Loss of function mutations of BCOR in classical Hodgkin lymphoma.
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Giefing M, Gearhart MD, Schneider M, Overbeck B, Klapper W, Hartmann S, Ustaszewski A, Weniger MA, Wiehle L, Hansmann ML, Melnick A, Béguelin W, Sundström C, Küppers R, Bardwell VJ, and Siebert R
- Subjects
- Animals, Humans, Loss of Function Mutation, Mice, Mutation, Polycomb Repressive Complex 1 metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Reed-Sternberg Cells pathology, Repressor Proteins genetics, Repressor Proteins metabolism, Hodgkin Disease pathology
- Abstract
BCOR is a component of a variant Polycomb repressive complex 1 (PRC1.1). PRC1 and PRC2 complexes together constitute a major gene regulatory system critical for appropriate cellular differentiation. The gene is upregulated in germinal center (GC) B cells and mutated in a number of hematologic malignancies. We report BCOR inactivating alterations in 4/7 classic Hodgkin lymphoma (cHL) cell lines, subclonal somatic mutations in Hodgkin and Reed-Sternberg (HRS) cells of 4/10 cHL cases, and deletions in HRS cells of 7/17 primary cHL cases. In mice, conditional loss of Bcor driven by AID-Cre in GC B cells resulted in gene expression changes of 46 genes (>2-fold) including upregulated Lef1 that encodes a transcription factor responsible for establishing T-cell identity and Il9r (interleukin-9 receptor), an important member of the cytokine network in cHL. Our findings suggest a role for BCOR loss in cHL pathogenesis and GC-B cell homeostasis.
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- 2022
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10. Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas.
- Author
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Hübschmann D, Kleinheinz K, Wagener R, Bernhart SH, López C, Toprak UH, Sungalee S, Ishaque N, Kretzmer H, Kreuz M, Waszak SM, Paramasivam N, Ammerpohl O, Aukema SM, Beekman R, Bergmann AK, Bieg M, Binder H, Borkhardt A, Borst C, Brors B, Bruns P, Carrillo de Santa Pau E, Claviez A, Doose G, Haake A, Karsch D, Haas S, Hansmann ML, Hoell JI, Hovestadt V, Huang B, Hummel M, Jäger-Schmidt C, Kerssemakers JNA, Korbel JO, Kube D, Lawerenz C, Lenze D, Martens JHA, Ott G, Radlwimmer B, Reisinger E, Richter J, Rico D, Rosenstiel P, Rosenwald A, Schillhabel M, Stilgenbauer S, Stadler PF, Martín-Subero JI, Szczepanowski M, Warsow G, Weniger MA, Zapatka M, Valencia A, Stunnenberg HG, Lichter P, Möller P, Loeffler M, Eils R, Klapper W, Hoffmann S, Trümper L, Küppers R, Schlesner M, and Siebert R
- Subjects
- Adult, B-Lymphocytes metabolism, Cell Line, Cell Line, Tumor, Genes, Immunoglobulin genetics, HeLa Cells, Hep G2 Cells, Human Umbilical Vein Endothelial Cells, Humans, Immunoglobulin Class Switching genetics, K562 Cells, MCF-7 Cells, Somatic Hypermutation, Immunoglobulin genetics, V(D)J Recombination genetics, Genome genetics, Germinal Center metabolism, Lymphoma, B-Cell genetics, Mutation genetics
- Abstract
B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR. We show that not only SHM, but presumably also CSR causes off-target mutations in non-IG genes. Kataegis clusters with high mutational density mainly affected early replicating regions and were enriched for SHM- and CSR-mediated off-target mutations. Moreover, they often co-occurred in loci physically interacting in the nucleus, suggesting that mutation hotspots promote increased mutation targeting of spatially co-localized loci (termed hypermutation by proxy). Only around 1% of somatic small variants were in protein coding sequences, but in about half of the driver genes, a contribution of B-cell specific mutational processes to their mutations was found. The B-cell-specific mutational processes contribute to both lymphoma initiation and intratumoral heterogeneity. Overall, we demonstrate that mutational processes involved in the development of gcBCL are more complex than previously appreciated, and that B cell-specific mutational processes contribute via diverse mechanisms to lymphomagenesis.
- Published
- 2021
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11. Human Cord Blood B Cells Differ from the Adult Counterpart by Conserved Ig Repertoires and Accelerated Response Dynamics.
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Budeus B, Kibler A, Brauser M, Homp E, Bronischewski K, Ross JA, Görgens A, Weniger MA, Dunst J, Kreslavsky T, Vitoriano da Conceição Castro S, Murke F, Oakes CC, Rusch P, Andrikos D, Kern P, Köninger A, Lindemann M, Johansson P, Hansen W, Lundell AC, Rudin A, Dürig J, Giebel B, Hoffmann D, Küppers R, and Seifert M
- Subjects
- Animals, Child, Child, Preschool, Female, Humans, Infant, Male, Mice, Mice, Congenic, Mice, Inbred NOD, Receptors, Antigen, B-Cell immunology, B-Lymphocytes immunology, Fetal Blood immunology, Immunoglobulins immunology
- Abstract
Neonatal and infant immune responses are characterized by a limited capability to generate protective Ab titers and memory B cells as seen in adults. Multiple studies support an immature or even impaired character of umbilical cord blood (UCB) B cells themselves. In this study, we provide a comprehensive molecular and functional comparison of B cell subsets from UCB and adult peripheral blood. Most UCB B cells have a mature, naive B cell phenotype as seen in adults. The UCB Ig repertoire is highly variable but interindividually conserved, as BCR clonotypes are frequently shared between neonates. Furthermore, UCB B cells show a distinct transcriptional program that confers accelerated responsiveness to stimulation and facilitated IgA class switching. Stimulation drives extensive differentiation into Ab-secreting cells, presumably limiting memory B cell formation. Humanized mice suggest that the distinctness of UCB versus adult B cells is already reflected by the developmental program of hematopoietic precursors, arguing for a layered B-1/B-2 lineage system as in mice, albeit our findings suggest only partial comparability to murine B-1 cells. Our study shows that UCB B cells are not immature or impaired but differ from their adult mature counterpart in a conserved BCR repertoire, efficient IgA class switching, and accelerated, likely transient response dynamics., (Copyright © 2021 by The American Association of Immunologists, Inc.)
- Published
- 2021
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12. Molecular biology of Hodgkin lymphoma.
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Weniger MA and Küppers R
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- Animals, B-Lymphocytes immunology, B-Lymphocytes metabolism, B-Lymphocytes pathology, Biomarkers, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic metabolism, Disease Management, Gene Expression Regulation, Neoplastic drug effects, Genetic Predisposition to Disease, Genetic Variation, Hodgkin Disease diagnosis, Hodgkin Disease metabolism, Hodgkin Disease therapy, Humans, Immune Evasion, Signal Transduction drug effects, Transcription Factors metabolism, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Disease Susceptibility, Hodgkin Disease etiology
- Abstract
Classical Hodgkin lymphoma (cHL) is unique among lymphoid malignancies in several key biological features. (i) The Hodgkin and Reed-Sternberg (HRS) tumor cells are rare among an extensive and complex microenvironment. (ii) They derive from B cells, but have largely lost the B-cell typical gene expression program. (iii) Their specific origin appears to be pre-apoptotic germinal center (GC) B cells. (iv) They consistently develop bi- or multinucleated Reed-Sternberg cells from mononuclear Hodgkin cells. (v) They show constitutive activation of numerous signaling pathways. Recent studies have begun to uncover the basis of these specific features of cHL: HRS cells actively orchestrate their complex microenvironment and attract many distinct subsets of immune cells into the affected tissues, to support their survival and proliferation, and to create an immunosuppressive environment. Reed-Sternberg cells are generated by incomplete cytokinesis and refusion of Hodgkin cells. Epstein-Barr virus (EBV) plays a major role in the rescue of crippled GC B cells from apoptosis and hence is a main player in early steps of lymphomagenesis of EBV
+ cHL cases. The analysis of the landscape of genetic lesions in HRS cells so far did not reveal any highly recurrent HRS cell-specific lesions, but major roles of genetic lesions in members of the NF-κB and JAK/STAT pathways and of factors of immune evasion. It is perhaps the combination of the genetic lesions and the peculiar cellular origin of HRS cells that are disease defining. A combination of such genetic lesions and multiple cellular interactions with cells in the microenvironment causes the constitutive activation of many signaling pathways, often interacting in complex fashions. In nodular lymphocyte predominant Hodgkin lymphoma, the GC B cell-derived tumor cells have largely retained their typical GC B-cell expression program and follicular microenvironment. For IgD-positive cases, bacterial antigen triggering has recently been implicated in early stages of its pathogenesis.- Published
- 2021
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13. Lymphocyte predominant cells detect Moraxella catarrhalis-derived antigens in nodular lymphocyte-predominant Hodgkin lymphoma.
- Author
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Thurner L, Hartmann S, Fadle N, Regitz E, Kemele M, Kim YJ, Bohle RM, Nimmesgern A, von Müller L, Kempf VAJ, Weniger MA, Neumann F, Schneider N, Vornanen M, Sundström C, de Leval L, Engert A, Eichenauer DA, Küppers R, Preuss KD, Hansmann ML, and Pfreundschuh M
- Subjects
- Adolescent, Adult, Aged, Autoantigens immunology, Cell Line, Tumor, Cell Proliferation, Child, DNA-Directed RNA Polymerases metabolism, Histocompatibility Antigens Class II metabolism, Hodgkin Disease blood, Humans, Immunoglobulin D metabolism, Immunoglobulin Fab Fragments immunology, Immunoglobulin Variable Region genetics, Male, Middle Aged, Models, Biological, Receptors, Antigen, B-Cell metabolism, Antigens, Bacterial immunology, B-Lymphocytes immunology, Hodgkin Disease immunology, Hodgkin Disease microbiology, Moraxella catarrhalis immunology
- Abstract
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma of B-cell origin with frequent expression of functional B-cell receptors (BCRs). Here we report that expression cloning followed by antigen screening identifies DNA-directed RNA polymerase beta' (RpoC) from Moraxella catarrhalis as frequent antigen of BCRs of IgD
+ LP cells. Patients show predominance of HLA-DRB1*04/07 and the IgVH genes encode extraordinarily long CDR3s. High-titer, light-chain-restricted anti-RpoC IgG1/κ-type serum-antibodies are additionally found in these patients. RpoC and MID/hag, a superantigen co-expressed by Moraxella catarrhalis that is known to activate IgD+ B cells by binding to the Fc domain of IgD, have additive activation effects on the BCR, the NF-κB pathway and the proliferation of IgD+ DEV cells expressing RpoC-specific BCRs. This suggests an additive antigenic and superantigenic stimulation of B cells with RpoC-specific IgD+ BCRs under conditions of a permissive MHC-II haplotype as a model of NLPHL lymphomagenesis, implying future treatment strategies.- Published
- 2020
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14. Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.
- Author
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López C, Kleinheinz K, Aukema SM, Rohde M, Bernhart SH, Hübschmann D, Wagener R, Toprak UH, Raimondi F, Kreuz M, Waszak SM, Huang Z, Sieverling L, Paramasivam N, Seufert J, Sungalee S, Russell RB, Bausinger J, Kretzmer H, Ammerpohl O, Bergmann AK, Binder H, Borkhardt A, Brors B, Claviez A, Doose G, Feuerbach L, Haake A, Hansmann ML, Hoell J, Hummel M, Korbel JO, Lawerenz C, Lenze D, Radlwimmer B, Richter J, Rosenstiel P, Rosenwald A, Schilhabel MB, Stein H, Stilgenbauer S, Stadler PF, Szczepanowski M, Weniger MA, Zapatka M, Eils R, Lichter P, Loeffler M, Möller P, Trümper L, Klapper W, Hoffmann S, Küppers R, Burkhardt B, Schlesner M, and Siebert R
- Subjects
- Adolescent, Alternative Splicing genetics, Amino Acid Sequence, Basic Helix-Loop-Helix Transcription Factors chemistry, Basic Helix-Loop-Helix Transcription Factors metabolism, Child, Child, Preschool, Chromosome Breakpoints, Cohort Studies, DNA Methylation genetics, DNA Mutational Analysis, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, INDEL Mutation genetics, Male, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Open Reading Frames genetics, Polymorphism, Single Nucleotide genetics, Proto-Oncogene Proteins c-myc genetics, Translocation, Genetic, Whole Genome Sequencing, Burkitt Lymphoma genetics, Genome, Human, Transcriptome genetics
- Abstract
Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.
- Published
- 2019
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15. Nuclear Fox(O1): not so fantastic.
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Weniger MA
- Subjects
- B-Lymphocytes, Cell Nucleus, Forkhead Box Protein O1, Germinal Center
- Abstract
Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests.
- Published
- 2018
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16. Expression profile of translation initiation factor eIF2B5 in diffuse large B-cell lymphoma and its correlation to clinical outcome.
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Unterluggauer JJ, Prochazka K, Tomazic PV, Huber HJ, Seeboeck R, Fechter K, Steinbauer E, Gruber V, Feichtinger J, Pichler M, Weniger MA, Küppers R, Sill H, Schicho R, Neumeister P, Beham-Schmid C, Deutsch AJA, and Haybaeck J
- Subjects
- B-Lymphocytes metabolism, B-Lymphocytes pathology, Female, Humans, Lymphoma, Large B-Cell, Diffuse metabolism, Male, Multigene Family, Prognosis, Transcription Factors metabolism, Gene Expression Regulation, Neoplastic, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse mortality, Transcription Factors genetics, Transcriptome
- Published
- 2018
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17. Human CD30+ B cells represent a unique subset related to Hodgkin lymphoma cells.
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Weniger MA, Tiacci E, Schneider S, Arnolds J, Rüschenbaum S, Duppach J, Seifert M, Döring C, Hansmann ML, and Küppers R
- Subjects
- B-Lymphocyte Subsets classification, B-Lymphocyte Subsets pathology, Genes, Immunoglobulin Heavy Chain, Genes, myc, Germinal Center immunology, Germinal Center pathology, Hodgkin Disease genetics, Hodgkin Disease pathology, Humans, Immunoglobulin Class Switching, Immunoglobulin Variable Region genetics, Immunologic Memory, Immunophenotyping, Lymph Nodes immunology, Lymph Nodes pathology, Mutation, Reed-Sternberg Cells immunology, Reed-Sternberg Cells pathology, Transcriptome, Tumor Necrosis Factor Receptor Superfamily, Member 7 metabolism, B-Lymphocyte Subsets immunology, Hodgkin Disease immunology, Ki-1 Antigen metabolism
- Abstract
Very few B cells in germinal centers (GCs) and extrafollicular (EF) regions of lymph nodes express CD30. Their specific features and relationship to CD30-expressing Hodgkin and Reed/Sternberg (HRS) cells of Hodgkin lymphoma are unclear but highly relevant, because numerous patients with lymphoma are currently treated with an anti-CD30 immunotoxin. We performed a comprehensive analysis of human CD30+ B cells. Phenotypic and IgV gene analyses indicated that CD30+ GC B lymphocytes represent typical GC B cells, and that CD30+ EF B cells are mostly post-GC B cells. The transcriptomes of CD30+ GC and EF B cells largely overlapped, sharing a strong MYC signature, but were strikingly different from conventional GC B cells and memory B and plasma cells, respectively. CD30+ GC B cells represent MYC+ centrocytes redifferentiating into centroblasts; CD30+ EF B cells represent active, proliferating memory B cells. HRS cells shared typical transcriptome patterns with CD30+ B cells, suggesting that they originate from these lymphocytes or acquire their characteristic features during lymphomagenesis. By comparing HRS to normal CD30+ B cells we redefined aberrant and disease-specific features of HRS cells. A remarkable downregulation of genes regulating genomic stability and cytokinesis in HRS cells may explain their genomic instability and multinuclearity.
- Published
- 2018
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18. An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma.
- Author
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Lollies A, Hartmann S, Schneider M, Bracht T, Weiß AL, Arnolds J, Klein-Hitpass L, Sitek B, Hansmann ML, Küppers R, and Weniger MA
- Subjects
- Carcinogenesis genetics, Carcinogenesis pathology, Cell Line, Tumor, Cell Proliferation genetics, Cell Survival, Gene Expression Regulation, Neoplastic genetics, Hodgkin Disease pathology, Humans, Janus Kinase 2 genetics, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Large-Cell, Anaplastic pathology, Oncogenes genetics, Promoter Regions, Genetic genetics, RNA, Small Interfering genetics, Signal Transduction genetics, Transcription Factor AP-1 genetics, Transcriptional Activation genetics, Basic-Leucine Zipper Transcription Factors genetics, Hodgkin Disease genetics, Lymphoma, Large-Cell, Anaplastic genetics, Proto-Oncogene Proteins c-myc genetics, STAT Transcription Factors genetics, Up-Regulation genetics
- Abstract
Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30
+ lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30+ diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas.- Published
- 2018
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19. Complex Immune Evasion Strategies in Classical Hodgkin Lymphoma.
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Wein F, Weniger MA, Höing B, Arnolds J, Hüttmann A, Hansmann ML, Hartmann S, and Küppers R
- Subjects
- Cell Line, Tumor, Gene Expression Profiling, Hodgkin Disease genetics, Hodgkin Disease pathology, Humans, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Signal Transduction, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Hodgkin Disease immunology, Immune Evasion genetics, Immune Evasion immunology
- Abstract
The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only about 1% Hodgkin and Reed/Sternberg (HRS) tumor cells. T cells are usually the largest population of cells in the cHL microenvironment, encompassing T helper (Th) cells, regulatory T cells (Tregs), and cytotoxic T cells. Th cells and Tregs presumably provide essential survival signals for HRS cells. Tregs are also involved in rescuing HRS cells from antitumor immune responses. An understanding of the immune evasion strategies of HRS cells is not only relevant for a characterization of the pathophysiology of cHL but is also clinically relevant, given the current treatment approaches targeting checkpoint inhibitors. Here, we characterized the cHL-specific CD4
+ T-cell infiltrate regarding its role in immune evasion. Global gene expression analysis of CD4+ Th cells and Tregs isolated from cHL lymph nodes and reactive tonsils revealed that Treg signatures were enriched in CD4+ Th cells of cHL. Hence, HRS cells may induce Treg differentiation in Th cells, a conclusion supported by in vitro studies with Th cells and cHL cell lines. We also found evidence for immune-suppressive purinergic signaling and a role of the inhibitory receptor-ligand pairs B- and T-cell lymphocyte attenuator-herpesvirus entry mediator and CD200R-CD200 in promoting immune evasion. Taken together, this study highlights the relevance of Treg induction and reveals new immune checkpoint-driven immune evasion strategies in cHL. Cancer Immunol Res; 5(12); 1122-32. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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20. Alterations of microRNA and microRNA-regulated messenger RNA expression in germinal center B-cell lymphomas determined by integrative sequencing analysis.
- Author
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Hezaveh K, Kloetgen A, Bernhart SH, Mahapatra KD, Lenze D, Richter J, Haake A, Bergmann AK, Brors B, Burkhardt B, Claviez A, Drexler HG, Eils R, Haas S, Hoffmann S, Karsch D, Klapper W, Kleinheinz K, Korbel J, Kretzmer H, Kreuz M, Küppers R, Lawerenz C, Leich E, Loeffler M, Mantovani-Loeffler L, López C, McHardy AC, Möller P, Rohde M, Rosenstiel P, Rosenwald A, Schilhabel M, Schlesner M, Scholz I, Stadler PF, Stilgenbauer S, Sungalee S, Szczepanowski M, Trümper L, Weniger MA, Siebert R, Borkhardt A, Hummel M, and Hoell JI
- Subjects
- Adolescent, Burkitt Lymphoma genetics, Child, Child, Preschool, Female, Gene Expression Profiling, Germinal Center, Humans, Infant, Infant, Newborn, Lymphoma, Follicular genetics, Lymphoma, Large B-Cell, Diffuse genetics, Male, MicroRNAs genetics, Mutation, RNA Editing, Lymphoma, B-Cell genetics, MicroRNAs metabolism, RNA, Messenger metabolism, Sequence Analysis, RNA methods
- Abstract
MicroRNA are well-established players in post-transcriptional gene regulation. However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential targets, whereas proof of the direct physical microRNA/target messenger RNA interaction is mostly lacking. Within the International Cancer Genome Consortium Project "Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing", we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas. Twenty-two miRNA separated Burkitt lymphomas from diffuse large B-cell lymphomas/follicular lymphomas, of which 13 have shown regulation by MYC. Moreover, we found expression of three hitherto unreported microRNA. Additionally, we detected recurrent mutations of hsa-miR-142 in diffuse large B-cell lymphomas and follicular lymphomas, and editing of the hsa-miR-376 cluster, providing evidence for microRNA editing in lymphomagenesis. To interrogate the direct physical interactions of microRNA with messenger RNA, we performed Argonaute-2 photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation experiments. MicroRNA directly targeted 208 messsenger RNA in the Burkitt lymphomas and 328 messenger RNA in the non-Burkitt lymphoma models. This integrative analysis discovered several regulatory pathways of relevance in lymphomagenesis including Ras, PI3K-Akt and MAPK signaling pathways, also recurrently deregulated in lymphomas by mutations. Our dataset reveals that messenger RNA deregulation through microRNA is a highly relevant mechanism in lymphomagenesis., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
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21. NF-κB deregulation in Hodgkin lymphoma.
- Author
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Weniger MA and Küppers R
- Subjects
- Epstein-Barr Virus Infections metabolism, Hodgkin Disease pathology, Hodgkin Disease virology, Humans, Mutation, NF-kappa B genetics, Signal Transduction genetics, Transcription Factors genetics, Transcription Factors metabolism, Tumor Microenvironment, Hodgkin Disease genetics, Hodgkin Disease metabolism, NF-kappa B metabolism
- Abstract
Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (HL) show constitutive activity of both the canonical and non-canonical NF-κB signaling pathways. The central pathogenetic role of this activity is indicated from studies with HL cell lines, which undergo apoptosis upon NF-κB inhibition. Multiple factors contribute to the strong NF-κB activity of HRS cells. This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3, NFKBIA), and copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14). In Epstein-Barr virus-positive cases of classical HL, the virus-encoded latent membrane protein 1 causes NF-κB activation by mimicking an active CD40 receptor. NF-κB activity is also seen in the tumor cells of the rare nodular lymphocyte predominant form of HL, but the causes for this activity are largely unclear., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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22. Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma.
- Author
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Saba NS, Liu D, Herman SE, Underbayev C, Tian X, Behrend D, Weniger MA, Skarzynski M, Gyamfi J, Fontan L, Melnick A, Grant C, Roschewski M, Navarro A, Beà S, Pittaluga S, Dunleavy K, Wilson WH, and Wiestner A
- Subjects
- Adenine analogs & derivatives, Amino Acid Substitution, Disease-Free Survival, Female, Humans, Male, Piperidines, Receptors, Antigen, B-Cell genetics, Survival Rate, Apoptosis drug effects, Apoptosis genetics, Drug Resistance, Neoplasm genetics, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell metabolism, Lymphoma, Mantle-Cell mortality, Mutation, Missense, Pyrazoles administration & dosage, Pyrimidines administration & dosage, Receptors, Antigen, B-Cell metabolism, Signal Transduction drug effects, Signal Transduction genetics, Transcription Factor RelA genetics, Transcription Factor RelA metabolism
- Abstract
To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-κB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-κB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-κB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-κB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors.
- Published
- 2016
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23. DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control.
- Author
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Kretzmer H, Bernhart SH, Wang W, Haake A, Weniger MA, Bergmann AK, Betts MJ, Carrillo-de-Santa-Pau E, Doose G, Gutwein J, Richter J, Hovestadt V, Huang B, Rico D, Jühling F, Kolarova J, Lu Q, Otto C, Wagener R, Arnolds J, Burkhardt B, Claviez A, Drexler HG, Eberth S, Eils R, Flicek P, Haas S, Humme M, Karsch D, Kerstens HHD, Klapper W, Kreuz M, Lawerenz C, Lenzek D, Loeffler M, López C, MacLeod RAF, Martens JHA, Kulis M, Martín-Subero JI, Möller P, Nage I, Picelli S, Vater I, Rohde M, Rosenstiel P, Rosolowski M, Russell RB, Schilhabel M, Schlesner M, Stadler PF, Szczepanowski M, Trümper L, Stunnenberg HG, Küppers R, Ammerpohl O, Lichter P, Siebert R, Hoffmann S, and Radlwimmer B
- Subjects
- Adolescent, Adult, Aged, B-Lymphocytes metabolism, Cell Line, Tumor, Child, Child, Preschool, Female, Genome, Human genetics, Germinal Center metabolism, High-Throughput Nucleotide Sequencing methods, Humans, Male, Middle Aged, Oncogene Proteins, Fusion genetics, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc genetics, Signal Transduction genetics, Translocation, Genetic, Young Adult, Burkitt Lymphoma genetics, DNA Methylation, Lymphoma, Follicular genetics, Mutation, Transcriptome genetics
- Abstract
Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.
- Published
- 2015
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24. Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma.
- Author
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Leshchenko VV, Kuo PY, Jiang Z, Weniger MA, Overbey J, Dunleavy K, Wilson WH, Wiestner A, and Parekh S
- Subjects
- Animals, Antineoplastic Agents pharmacology, Azacitidine analogs & derivatives, Azacitidine chemistry, Cell Line, Tumor, Cell Survival, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, DNA Methylation, Decitabine, Epigenesis, Genetic, Female, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, Proteasome Inhibitors chemistry, Real-Time Polymerase Chain Reaction, Recurrence, Bortezomib pharmacology, Drug Resistance, Neoplasm, Lymphoma, Mantle-Cell drug therapy, Proto-Oncogene Proteins c-bcl-2 metabolism
- Abstract
Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. Given that a large proportion of patients will not respond, BZM resistance is a significant barrier to use this agent in MCL. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. Genome-wide DNA methylation analysis using a NimbleGen array platform revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. These findings suggest a role for dynamic Noxa methylation for the therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients.
- Published
- 2015
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25. MINCR is a MYC-induced lncRNA able to modulate MYC's transcriptional network in Burkitt lymphoma cells.
- Author
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Doose G, Haake A, Bernhart SH, López C, Duggimpudi S, Wojciech F, Bergmann AK, Borkhardt A, Burkhardt B, Claviez A, Dimitrova L, Haas S, Hoell JI, Hummel M, Karsch D, Klapper W, Kleo K, Kretzmer H, Kreuz M, Küppers R, Lawerenz C, Lenze D, Loeffler M, Mantovani-Löffler L, Möller P, Ott G, Richter J, Rohde M, Rosenstiel P, Rosenwald A, Schilhabel M, Schneider M, Scholz I, Stilgenbauer S, Stunnenberg HG, Szczepanowski M, Trümper L, Weniger MA, Hoffmann S, Siebert R, and Iaccarino I
- Subjects
- Base Sequence, Binding Sites, Cell Cycle, Cell Line, Cell Line, Tumor, Cell Survival, Chromatin metabolism, Gene Expression Profiling, Humans, In Situ Hybridization, Fluorescence, Molecular Sequence Data, Neoplasms metabolism, Promoter Regions, Genetic, RNA, Small Interfering metabolism, Sequence Homology, Nucleic Acid, Burkitt Lymphoma metabolism, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Lymphoma, B-Cell metabolism, Proto-Oncogene Proteins c-myc metabolism, RNA, Long Noncoding metabolism
- Abstract
Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.
- Published
- 2015
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26. A large fraction of human tonsillar B cells expressing CD27 are germinal center B cells.
- Author
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Przekopowitz M, Küppers R, and Weniger MA
- Subjects
- Humans, B-Lymphocyte Subsets immunology, Immunologic Memory, Palatine Tonsil immunology
- Published
- 2015
- Full Text
- View/download PDF
27. New molecular targets in mantle cell lymphoma.
- Author
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Parekh S, Weniger MA, and Wiestner A
- Subjects
- Humans, Lymphoma, Mantle-Cell metabolism, Antineoplastic Agents therapeutic use, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell pathology, Molecular Targeted Therapy, Signal Transduction drug effects
- Abstract
Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by aberrant expression of cyclin D1 due to the translocation t(11;14). Epigenomic and genomic lesions in pathways regulating B-cell activation, cell cycle progression, protein homeostasis, DNA damage response, cell proliferation and apoptosis contribute to its pathogenesis. While patients typically respond to first-line chemotherapy, relapse is the rule resulting in a median survival of 5-7 years. The PI3K/AKT/mTOR appears as a key pathway in the pathogenesis and can be targeted with small molecules. Most experience is with mTOR inhibitors of the rapamycin class. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 are novel options to more effectively target this pathway. Bruton's tyrosine kinase inhibition by PCI-32765 has promising activity and indicates immunoreceptor signaling as a novel therapeutic target. Up to 50% of relapsed patients respond to the proteasome inhibitor bortezomib suggesting that MCL may be particularly sensitive to disruption of protein homeostasis and/or induction of oxidative stress. Recent work has focused on elucidating the mechanism of bortezomib-induced cytotoxicity and the development of second-generation proteasome inhibitors. DNA hypomethylating agents and histone deacetylase inhibitors effect epigenetic de-repression of aberrantly silenced genes. These epigenetic pharmaceuticals and HSP90 inhibitors can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients a chance to benefit from these advances and is essential to maintain the momentum of progress. Innovative trial designs may be needed to expedite the clinical development of these targeted agents., (Published by Elsevier Ltd.)
- Published
- 2011
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28. Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia.
- Author
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Aue G, Du Y, Cleveland SM, Smith SB, Davé UP, Liu D, Weniger MA, Metais JY, Jenkins NA, Copeland NG, and Dunbar CE
- Subjects
- Animals, Bone Marrow Transplantation, Cells, Cultured, Disease Models, Animal, Epistasis, Genetic physiology, Gene Expression Profiling, Gene Expression Regulation, Leukemic, HL-60 Cells, Humans, Leukemia, Myeloid mortality, Leukemia, Myeloid pathology, Leukemia, Myeloid therapy, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microarray Analysis, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins physiology, SOXC Transcription Factors genetics, SOXC Transcription Factors metabolism, Trans-Activators metabolism, Trans-Activators physiology, Haploinsufficiency physiology, Leukemia, Myeloid genetics, Proto-Oncogene Proteins genetics, SOXC Transcription Factors physiology, Trans-Activators genetics
- Abstract
Cooperation of multiple mutations is thought to be required for cancer development. In previous studies, murine myeloid leukemias induced by transducing wild-type bone marrow progenitors with a SRY sex determining region Y-box 4 (Sox4)-expressing retrovirus frequently carried proviral insertions at Sfpi1, decreasing its mRNA levels, suggesting that reduced Sfpi1 expression cooperates with Sox4 in myeloid leukemia induction. In support of this hypothesis, we show here that mice receiving Sox4 virus-infected Sfpi1(ko/+) bone marrow progenitors developed myeloid leukemia with increased penetrance and shortened latency. Interestingly, Sox4 expression further decreased Sfpi1 transcription. Ectopic SOX4 expression reduced endogenous PU.1 mRNA levels in HL60 promyelocytes, and decreased Sfpi1 mRNA levels were also observed in the spleens of leukemic and preleukemic mice receiving Sox4 virus-infected wild-type bone marrow cells. In addition, Sox4 protein bound to a critical upstream regulatory element of Sfpi1 in ChIP assays. Such cooperation probably occurs in de novo human acute myeloid leukemias, as an analysis of 285 acute myeloid leukemia patient samples found a significant negative correlation between SOX4 and PU.1 expression. Our results establish a novel cooperation between Sox4 and reduced Sfpi1 expression in myeloid leukemia development and suggest that SOX4 could be an important new therapeutic target in human acute myeloid leukemia.
- Published
- 2011
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29. Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma.
- Author
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Weniger MA, Rizzatti EG, Pérez-Galán P, Liu D, Wang Q, Munson PJ, Raghavachari N, White T, Tweito MM, Dunleavy K, Ye Y, Wilson WH, and Wiestner A
- Subjects
- Antineoplastic Agents pharmacology, Boronic Acids pharmacology, Bortezomib, Cell Survival, Drug Resistance, Neoplasm, Endoplasmic Reticulum drug effects, Gene Expression Profiling, Humans, Lymphoma, Mantle-Cell metabolism, NF-E2-Related Factor 2 pharmacology, Oxidative Stress drug effects, Proteasome Endopeptidase Complex metabolism, Pyrazines pharmacology, Stress, Physiological drug effects, Transcription, Genetic drug effects, Tumor Cells, Cultured, Antineoplastic Agents therapeutic use, Antioxidants pharmacology, Boronic Acids therapeutic use, Lymphoma, Mantle-Cell drug therapy, Proteasome Inhibitors, Pyrazines therapeutic use
- Abstract
Purpose: Proteasome inhibition disrupts protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. We used gene expression profiling to investigate the connection between proteasome inhibition, cellular response, and clinical efficacy., Experimental Design: We assessed transcriptional changes in primary tumor cells from five patients during treatment with bortezomib in vivo, and in 10 MCL cell lines exposed to bortezomib in vitro, on Affymetrix microarrays. Key findings were confirmed by western blotting., Results: MCL cell lines exposed to bortezomib in vitro showed upregulation of endoplasmic reticulum and oxidative stress response pathways. Gene expression changes were strongest in bortezomib-sensitive cells and these cells were also more sensitive to oxidative stress induced by H2O2. Purified tumor cells obtained at several timepoints during bortezomib treatment in 5 previously untreated patients with leukemic MCL showed strong activation of the antioxidant response controlled by NRF2. Unexpectedly, activation of this homeostatic program was significantly stronger in tumors with the best clinical response. Consistent with its proapoptotic function, we found upregulation of NOXA in circulating tumor cells of responding patients. In resistant cells, gene expression changes in response to bortezomib were limited and upregulation of NOXA was absent. Interestingly, at baseline, bortezomib-resistant cells displayed a relatively higher expression of the NRF2 gene-expression signature than sensitive cells (P < 0.001)., Conclusion: Bortezomib triggers an oxidative stress response in vitro and in vivo. High cellular antioxidant capacity contributes to bortezomib resistance., (©2011 AACR.)
- Published
- 2011
- Full Text
- View/download PDF
30. Molecular targeted approaches in mantle cell lymphoma.
- Author
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Weniger MA and Wiestner A
- Subjects
- Clinical Trials as Topic, Humans, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell metabolism, Molecular Targeted Therapy methods
- Abstract
Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by the translocation t(11;14) that leads to aberrant expression of cyclin D1. Response to first-line chemotherapy is good, but most patients relapse, resulting in a median survival of 5 to 7 years. The important PI3K/AKT/mTOR pathway can be targeted with small molecules. mTOR inhibitors have clinical activity and temsirolimus has been approved in Europe. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 offer additional means to target the pathway. Promising results with the BTK inhibitor PCI-32765 suggest that B-cell receptor signaling could play a role. For unknown reasons, MCL appears to be particularly sensitive to disruption of protein homeostasis. The proteasome inhibitor bortezomib achieves responses in up to 50% of relapsed patients. Much work has been done in elucidating the mechanism of its cytotoxicity, its incorporation into combination therapies, and the development of second-generation proteasome inhibitors. Deacetylase and HSP90 inhibitors are also promising classes of drugs that can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients an immediate chance to benefit from these advances and is essential to maintain the momentum of progress., (Published by Elsevier Inc.)
- Published
- 2011
- Full Text
- View/download PDF
31. Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation.
- Author
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Pérez-Galán P, Mora-Jensen H, Weniger MA, Shaffer AL 3rd, Rizzatti EG, Chapman CM, Mo CC, Stennett LS, Rader C, Liu P, Raghavachari N, Stetler-Stevenson M, Yuan C, Pittaluga S, Maric I, Dunleavy KM, Wilson WH, Staudt LM, and Wiestner A
- Subjects
- ADP-ribosyl Cyclase 1 biosynthesis, Aged, Blotting, Western, Bortezomib, Cell Differentiation, Cell Line, Tumor, Cell Separation, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Gene Expression Profiling, Humans, Interferon Regulatory Factors biosynthesis, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell metabolism, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Proteasome Endopeptidase Complex drug effects, Proteasome Endopeptidase Complex genetics, Proteasome Endopeptidase Complex metabolism, Antineoplastic Agents pharmacology, Boronic Acids pharmacology, Drug Resistance, Neoplasm physiology, Lymphoma, Mantle-Cell drug therapy, Plasma Cells pathology, Pyrazines pharmacology
- Abstract
Bortezomib induces remissions in 30%-50% of patients with relapsed mantle cell lymphoma (MCL). Conversely, more than half of patients' tumors are intrinsically resistant to bortezomib. The molecular mechanism of resistance has not been defined. We generated a model of bortezomib-adapted subclones of the MCL cell lines JEKO and HBL2 that were 40- to 80-fold less sensitive to bortezomib than the parental cells. Acquisition of bortezomib resistance was gradual and reversible. Bortezomib-adapted subclones showed increased proteasome activity and tolerated lower proteasome capacity than the parental lines. Using gene expression profiling, we discovered that bortezomib resistance was associated with plasmacytic differentiation, including up-regulation of IRF4 and CD38 and expression of CD138. In contrast to plasma cells, plasmacytic MCL cells did not increase immunoglobulin secretion. Intrinsically bortezomib-resistant MCL cell lines and primary tumor cells from MCL patients with inferior clinical response to bortezomib also expressed plasmacytic features. Knockdown of IRF4 was toxic for the subset of MCL cells with plasmacytic differentiation, but only slightly sensitized cells to bortezomib. We conclude that plasmacytic differentiation in the absence of an increased secretory load can enable cells to withstand the stress of proteasome inhibition. Expression of CD38 and IRF4 could serve as markers of bortezomib resistance in MCL. This study has been registered at http://clinicaltrials.gov as NCT00131976.
- Published
- 2011
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32. The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group.
- Author
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Wang Q, Shinkre BA, Lee JG, Weniger MA, Liu Y, Chen W, Wiestner A, Trenkle WC, and Ye Y
- Subjects
- Adenosine Triphosphatases metabolism, Cluster Analysis, Endoplasmic Reticulum metabolism, Gene Expression Profiling, HEK293 Cells, HeLa Cells, Humans, Hydrazones chemistry, Hydrazones metabolism, Hydroxyurea chemistry, Hydroxyurea metabolism, Hydroxyurea pharmacology, Intracellular Membranes metabolism, Molecular Structure, Nuclear Proteins metabolism, Oligonucleotide Array Sequence Analysis, Protein Binding, Protein Transport drug effects, Reverse Transcriptase Polymerase Chain Reaction, Surface Plasmon Resonance, Adenosine Triphosphatases antagonists & inhibitors, Hydrazones pharmacology, Hydroxyurea analogs & derivatives, Nuclear Proteins antagonists & inhibitors
- Abstract
Background: Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death in cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anti-cancer activities resembling that of Bortezomib., Methodology and Principal Findings: Here we developed in vitro binding and cell-based functional assays to demonstrate that a nitrofuran-containing (NFC) group in EerI is the functional domain responsible for the cytotoxicity. Using both SPR and pull down assays, we show that EerI directly binds the p97 ATPase, an essential component of the ERAD machinery, via the NFC domain. An aromatic domain in EerI, although not required for p97 interaction, can localize EerI to the ER membrane, which improves its target specificity. Substitution of the aromatic module with another benzene-containing domain that maintains membrane localization generates a structurally distinct compound that nonetheless has similar biologic activities as EerI., Conclusions and Significance: Our findings reveal a class of bifunctional chemical agents that can preferentially inhibit membrane-bound p97 to disrupt ER homeostasis and to induce tumor cell death. These results also suggest that the AAA ATPase p97 may be a potential drug target for cancer therapeutics.
- Published
- 2010
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33. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma.
- Author
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Leshchenko VV, Kuo PY, Shaknovich R, Yang DT, Gellen T, Petrich A, Yu Y, Remache Y, Weniger MA, Rafiq S, Suh KS, Goy A, Wilson W, Verma A, Braunschweig I, Muthusamy N, Kahl BS, Byrd JC, Wiestner A, Melnick A, and Parekh S
- Subjects
- Antigens, CD genetics, Antigens, Neoplasm genetics, Biomarkers, Tumor metabolism, Cell Proliferation, Cells, Cultured, Drug Discovery, Fluorescent Antibody Technique, Gene Expression Profiling, Humans, Immunoenzyme Techniques, Lymphoma, Mantle-Cell pathology, Oligonucleotide Array Sequence Analysis, Tetraspanins, Biomarkers, Tumor genetics, DNA Methylation, Drug Design, Genome, Human, Lymphoma, Mantle-Cell genetics
- Abstract
Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a small modular immunopharmaceutical (CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the histone deacetylase inhibitor suberoylanilide hydroxamic acid in induction of the hypermethylated genes and anti-MCL cytotoxicity. Our data show prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.
- Published
- 2010
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34. ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells.
- Author
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Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, and Ye Y
- Subjects
- Adaptor Proteins, Signal Transducing, Antineoplastic Agents pharmacology, Boronic Acids pharmacology, Bortezomib, Cell Line, Cell Line, Tumor, HeLa Cells, Humans, Hydrazones metabolism, Hydroxyurea analogs & derivatives, Hydroxyurea metabolism, Neoplasms metabolism, Pyrazines pharmacology, Transcription, Genetic, Adaptor Proteins, Vesicular Transport metabolism, Endoplasmic Reticulum metabolism, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Proteasome Endopeptidase Complex chemistry, Ubiquitin chemistry
- Abstract
The ubiquitin-proteasome system has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks endoplasmic reticulum (ER)-associated protein degradation, has antitumor and biologic activities similar to bortezomib and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the up-regulation of the Bcl-2 homology3 (BH3)-only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes. First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anticancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.
- Published
- 2009
- Full Text
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35. Deletion analysis and alternative splicing define a transactivation inhibitory domain in human oncoprotein REL.
- Author
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Leeman JR, Weniger MA, Barth TF, and Gilmore TD
- Subjects
- Animals, Biomarkers, Tumor genetics, Cell Transformation, Neoplastic genetics, Cells, Cultured, Chickens, Humans, Lymphoma genetics, Oncogene Proteins v-rel genetics, Promoter Regions, Genetic genetics, Protein Structure, Tertiary genetics, Spleen metabolism, Alternative Splicing genetics, Biomarkers, Tumor biosynthesis, Cell Transformation, Neoplastic metabolism, Exons, Gene Expression Regulation, Neoplastic genetics, Lymphoma metabolism, Oncogene Proteins v-rel biosynthesis, Transcriptional Activation genetics
- Abstract
Misregulation of REL, a nuclear factor-kappaB family transcription factor, has been implicated in several human lymphoid malignancies. REL has a conserved N-terminal DNA-binding/dimerization domain called the Rel homology domain (RHD) and a C-terminal transactivation domain (TAD). Here, we define the sequences (amino acids (aa) 323-422) between the RHD and TAD as a REL inhibitory domain (RID) because deletion of these sequences increases both REL transactivation and DNA binding. Furthermore, we have characterized two REL mRNA splice variants that encode proteins with alterations near RID: one lacking exon 9 sequences (aa 308-330; RELDelta9) and one with an exonized Alu fragment insertion of 32 aa after aa 307 (REL+Alu). Deletion of RID or exon 9-encoded sequences increases transactivation by GAL4-REL by approximately threefold. Moreover, deletion of RID or exon 9 sequences increases transactivation by full-length REL from certain kappaB site-containing promoters and increases DNA binding by REL. Deletion of RID does not affect REL's ability to transform chicken spleen cells. Reverse transcriptase-polymerase chain reaction analysis of mRNA from both primary lymphoma samples and several transformed tissue culture cell lines indicates that the RELDelta9 splice variant is preferentially expressed in lymphoma, suggesting that the REL transcript lacking exon 9 could serve as a marker for certain types of lymphoid tumors.
- Published
- 2008
- Full Text
- View/download PDF
36. Noxa mediates bortezomib induced apoptosis in both sensitive and intrinsically resistant mantle cell lymphoma cells and this effect is independent of constitutive activity of the AKT and NF-kappaB pathways.
- Author
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Rizzatti EG, Mora-Jensen H, Weniger MA, Gibellini F, Lee E, Daibata M, Lai R, and Wiestner A
- Subjects
- Bortezomib, Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Lymphoma, Mantle-Cell drug therapy, Proto-Oncogene Proteins c-bcl-2 genetics, Signal Transduction, Up-Regulation, Apoptosis drug effects, Boronic Acids pharmacology, Lymphoma, Mantle-Cell pathology, NF-kappa B metabolism, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-bcl-2 physiology, Pyrazines pharmacology
- Abstract
Bortezomib is more active against mantle cell lymphoma (MCL) than against most other lymphoma subtypes. Nevertheless, up to half of patients with MCL have bortezomib resistant disease. Factors contributing to intrinsic resistance to bortezomib have not been determined. Here we used a panel of eight bortezomib sensitive (median IC(50) 5.9 nM) and three relatively bortezomib resistant cell lines (median IC(50) 12.9 nM) to investigate differences in tumor biology that could determine sensitivity to bortezomib. Bortezomib effectively inhibited high baseline proteasome activity and induced a comparable degree of proteasome inhibition in both sensitive and resistant cells. At 10 nM, bortezomib induced the proapoptotic BH3-only protein Noxa in sensitive but not resistant cells. At higher concentrations of bortezomib, however, Noxa was also upregulated in resistant cells and this effect was sufficient to induce apoptosis. Silencing of Noxa with siRNA rescued these cells from apoptosis, arguing against a defect in Noxa regulation or function as the basis of bortezomib resistance. Bortezomib was equally effective against cells with high and low constitutive NF-kappaB signaling. Also, sensitive and resistant MCL cell lines showed comparable activation of the AKT pathway. We conclude that bortezomib can overcome classic mechanisms of resistance to apoptosis and that determinants of bortezomib sensitivity in MCL are due to differences in signaling or stress pathways upstream of Noxa.
- Published
- 2008
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37. Gains of REL in primary mediastinal B-cell lymphoma coincide with nuclear accumulation of REL protein.
- Author
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Weniger MA, Gesk S, Ehrlich S, Martin-Subero JI, Dyer MJ, Siebert R, Möller P, and Barth TF
- Subjects
- Gene Expression Regulation, Neoplastic physiology, Humans, Lymphoma, B-Cell genetics, Mediastinal Neoplasms genetics, Proto-Oncogene Proteins c-rel genetics, Cell Nucleus metabolism, Lymphoma, B-Cell metabolism, Mediastinal Neoplasms metabolism, Proto-Oncogene Proteins c-rel metabolism
- Abstract
Gains or amplifications of the REL locus are frequently seen in primary mediastinal B-cell lymphoma (PMBL). In classical Hodgkin's lymphoma, genomic overrepresentation of REL correlated with nuclear REL protein accumulation. To investigate the correlation between REL gene copies and its RNA and protein expression in PMBL, we analyzed genomic, transcriptional, and protein levels in 20 PMBLs and the PMBL derived cell lines MedB-1 and Karpas1106P. We found gains/amplifications in 75% of the PMBLs by fluorescence in situ hybridization (FISH) and genomic REL overrepresentation in the PMBL lines. Three of the five PMBLs with amplifications displayed elevated REL transcripts, while only 3/10 PMBLs with gains showed increased REL transcripts by real-time PCR. One PMBL without gains displayed increased REL transcription. REL protein expression exhibited a variable pattern across the PMBLs except for a single case that was completely negative by immunohistochemistry despite having gained REL. Although transcript levels were generally low and nuclear REL staining was weak in the lymphoma cell lines, these nevertheless exhibited high NF-kappaB activation. By fluorescence immunophenotyping and interphase cytogenetics as a tool for investigation of neoplasms, genomic gains/amplifications of REL significantly correlated with nuclear REL expression (P < 0.05). In conclusion, the frequent genomic overrepresentation of REL in PMBL does not necessarily trigger an increased transcription/translation of REL. However, combined genomic and protein analysis revealed a significant association of gained REL and nuclear REL accumulation at the single cell level., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2007
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38. Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein are frequent in primary mediastinal B-cell lymphoma.
- Author
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Weniger MA, Pulford K, Gesk S, Ehrlich S, Banham AH, Lyne L, Martin-Subero JI, Siebert R, Dyer MJ, Möller P, and Barth TF
- Subjects
- Cell Nucleus metabolism, Humans, Lymphoma, B-Cell metabolism, Lymphoma, B-Cell physiopathology, Mediastinal Neoplasms metabolism, Mediastinal Neoplasms physiopathology, Proto-Oncogene Mas, Repressor Proteins, Carrier Proteins genetics, Carrier Proteins metabolism, Gene Expression Regulation, Neoplastic, Lymphoma, B-Cell genetics, Mediastinal Neoplasms genetics, Nuclear Proteins genetics, Nuclear Proteins metabolism
- Published
- 2006
- Full Text
- View/download PDF
39. Genomic alterations in Hodgkin's lymphoma.
- Author
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Weniger MA, Barth TF, and Möller P
- Subjects
- Chromosomes, Human, Pair 2 genetics, Chromosomes, Human, Pair 9 genetics, Humans, Lymphoma, B-Cell genetics, Nucleic Acid Hybridization methods, Chromosome Aberrations, Epigenesis, Genetic, Gene Expression Regulation, Leukemic, Genomic Instability, Hodgkin Disease genetics
- Abstract
Cytogenetic analysis of Hodgkin's lymphoma (HL) is hampered by the scarcity of neoplastic cells within a sea of reactive cells. There is accumulating evidence that HL represents 2 disease entities, classic HL (cHL) with its morphologic variants and nodular lymphocyte predominant HL (NLPHL). This subdivision, initially worked out in morphologic and immunohistochemical studies, has been further substantiated by molecular cytogenetic investigations. Two recurrent chromosomal aberrations, namely gains of 2p13-p16 and 9p24, have been found by comparative genomic hybridization analysis in microdissected cells from cHL patients as well as in cHL cell lines, but not in NLPHL cells. The available cHL cell lines are remarkably heterogeneous in their karyotypes, suggesting profound genomic instability leading to numeric chromosomal aberration and multiple chromosomal breaks and translocations. In this article, we review genomic aberrations that may contribute to the development and maintenance of the morphologic and clinical presentation of these beta-cell lymphoma entities. Furthermore, we delineate current data on the genomic changes observed in the neoplastic cells of HL that are created by epigenetic mechanisms, which are alternative mechanisms that regulate the expression of relevant genes.
- Published
- 2006
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40. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation.
- Author
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Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K, Mattfeldt T, Barth TF, and Möller P
- Subjects
- Amino Acid Sequence, Base Sequence, Hodgkin Disease metabolism, Humans, Lasers, Molecular Sequence Data, Phosphorylation, Reed-Sternberg Cells, Sequence Homology, Amino Acid, Suppressor of Cytokine Signaling 1 Protein, Cell Nucleus metabolism, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Hodgkin Disease genetics, Intracellular Signaling Peptides and Proteins genetics, Mutation, Repressor Proteins genetics, STAT5 Transcription Factor metabolism, Suppressor of Cytokine Signaling Proteins genetics
- Abstract
The suppressors of cytokine signaling (SOCS) are critically involved in the regulation of cellular proliferation, survival, and apoptosis via cytokine-induced JAK/STAT signaling. SOCS-1 silencing by aberrant DNA methylation contributes to oncogenesis in various B-cell neoplasias and carcinomas. Recently, we showed an alternative loss of SOCS-1 function due to deleterious SOCS-1 mutations in a major subset of primary mediastinal B-cell lymphoma (PMBL) and in the PMBL line MedB-1, and a biallelic SOCS-1 deletion in PMBL line Karpas1106P. For both cell lines our previous data demonstrated retarded JAK2 degradation and sustained phospho-JAK2 action leading to enhanced DNA binding of phospho-STAT5. Here, we analysed SOCS-1 in laser-microdissected Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We detected SOCS-1 mutations in HRS cells of eight of 19 cHL samples and in three of five Hodgkin lymphoma (HL)-derived cell lines by sequencing analysis. Moreover, we found a significant association between mutated SOCS-1 of isolated HRS cells and nuclear phospho-STAT5 accumulation in HRS cells of cHL tumor tissue (P < 0.01). Collectively, these findings support the concept that PMBL and cHL share many overlapping features, and that defective tumor suppressor gene SOCS-1 triggers an oncogenic pathway operative in both lymphomas.
- Published
- 2006
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41. Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein.
- Author
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Melzner I, Weniger MA, Bucur AJ, Brüderlein S, Dorsch K, Hasel C, Leithäuser F, Ritz O, Dyer MJ, Barth TF, and Möller P
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Janus Kinase 2, Microsatellite Repeats, Mutation, Signal Transduction, Suppressor of Cytokine Signaling 1 Protein, Tumor Cells, Cultured, Chromosomes, Human, Pair 16, Gene Deletion, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins physiology, Lymphoma, B-Cell genetics, Mediastinal Neoplasms genetics, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins metabolism, Repressor Proteins genetics, Repressor Proteins physiology, Suppressor of Cytokine Signaling Proteins genetics, Suppressor of Cytokine Signaling Proteins physiology
- Abstract
Activity of Janus kinase 2 (JAK2) in the JAK2/STAT5 signaling pathway is critically controlled by suppressor of cytokine signaling-1 (SOCS-1). We have previously shown that SOCS-1 is biallelically mutated in the primary mediastinal B-cell lymphoma (PMBL) cell line MedB-1, resulting in impaired JAK2 degradation and sustained phospho-JAK2 action. SOCS-1 is frequently mutated in PMBL tumor primaries. Here, we report that the PMBL cell line Karpas1106P has a biallelic deletion of the SOCS-1 region on chromosome 16p13.13. By fluorescence in situ hybridization and microsatellite analysis, this deletion was narrowed down to a range of 650 kb to 1.48 Mb. Like MedB-1, Karpas1106P harbors gains of the JAK2 gene on chromosomal region 9p24 and elevated levels of JAK2 mRNA. Nevertheless, JAK2 protein was not increased but constitutively phosphorylated in Karpas1106P cells. In analogy to MedB-1 cells, Karpas1106P cells exhibited a retarded degradation of de novo synthesized JAK2 protein revealed by pulse/chase experiments. Therefore, we conclude that loss of SOCS-1 function either by mutation or by the complete deletion of the gene plays an important role in the dysregulation of JAK/STAT signaling in Karpas1106P and PMBL., (Copyright (c) 2005 Wiley-Liss, Inc.)
- Published
- 2006
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42. Absence of the JAK2 V617F activating mutation in classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma.
- Author
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Melzner I, Weniger MA, Menz CK, and Möller P
- Subjects
- Base Sequence, Humans, Janus Kinase 2, Molecular Sequence Data, Mutation, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins metabolism, Hodgkin Disease genetics, Lymphoma, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse genetics, Mediastinal Neoplasms genetics, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics
- Published
- 2006
- Full Text
- View/download PDF
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