Gene Expression Profiling of B Cell Lymphoma in Dogs Reveals Dichotomous Metabolic Signatures Distinguished by Oxidative Phosphorylation (original) (raw)
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Metabolic Signatures Uncover Distinct Targets in Molecular Subsets of Diffuse Large B Cell Lymphoma
Cancer Cell, 2012
Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels. Moreover, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications.
State of the Art and Comparative Aspects in Canine Lymphoma!
2013
s of invited lectures Workshop Proceedings Page 5 Abstracts of invited lectures SESSION ON PATHOGENESIS Chairs: Hugo Murua Escobar, Franco Guscetti 01 Comparative Transcriptional Analysis of Canine and Human Diffuse Large B Cell Lymphoma (DLBCL). Molecular Signatures of NF-κB Activation and Sub-Classification of DLBCL Ted Hupp Edinburgh Cancer Research UK Centre, Edinburgh, United Kingdom E-mail: Ted.Hupp@ed.ac.uk Hupp T.1, Mudaliar, M.A.V.2, Haggart, R.D.2, Miele, G.3, Sellar, G.3, Tan, K.A.L.4, Goodlad, J.R.5, Milne, E.4, Vail, D.M.6, Kurzman, I.6, Crowther, D.3, and Argyle D.J.4 1Edinburgh Cancer Research UK Centre, Edinburgh EH4 2XR, UK; 2Translational Medicine Research Collaboration, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK; 3Pfizer Inc, Translational Medicine Research Collaboration, Ninewells Hospital, Dundee DD1 9SY, UK; 4Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK; 4Western ...
Molecular Profiling Reveals Prognostically Significant Subtypes of Canine Lymphoma
Veterinary Pathology, 2013
We performed genomewide gene expression analysis of 35 samples representing 6 common histologic subtypes of canine lymphoma and bioinformatics analyses to define their molecular characteristics. Three major groups were defined on the basis of gene expression profiles: (1) low-grade T-cell lymphoma, composed entirely by T-zone lymphoma; (2) high-grade T-cell lymphoma, consisting of lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified; and (3) B-cell lymphoma, consisting of marginal B-cell lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. Interspecies comparative analyses of gene expression profiles also showed that marginal B-cell lymphoma and diffuse large B-cell lymphoma in dogs and humans might represent a continuum of disease with similar drivers. The classification of these diverse tumors into 3 subgroups was prognostically significant, as the groups were directly correlated with event-free survival. Finally, we developed a benchtop diagnostic test based on expression of 4 genes that can robustly classify canine lymphomas into one of these 3 subgroups, enabling a direct clinical application for our results.
Oxidative stress in lymphoma: similarities and differences between dog and human
Comparative Clinical Pathology, 2013
In the last 20 years, an increasing interest toward oxidative stress has been documented in order to investigate their direct or indirect involvement in several mechanisms regarding oncogenesis and lymphomas in particular. The aim of this paper was to evaluate oxidative stress in dogs affected by malignant lymphoma in comparison to a control group, to investigate what factors can affect this status, and to point out similarities and differences with human. Forty-eight samples from four subjects, affected by high-grade centroblastic polymorphic lymphoma and receiving a standard chemotherapy, have been processed for derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) tests. The obtained data show a condition of oxidative stress in dogs with lymphoma, with a significant increase in reactive oxygen species (ROS) plasma levels and a decrease in antioxidant capacity. No significant differences emerged on the basis of remission. Further results of canine studies about oxidative status in lymphomas could be a model for human, according to analogy between them.
Development and characterization of 5 canine B-cell lymphoma cell lines
Leukemia Research, 2012
Canine and human lymphoma share similar characteristics in disease development and response to therapy. Translational research can be furthered using tools such as canine cell lines to model therapeutic compounds and strategies. We developed 5 B-cell lymphoma cell lines from dogs with confirmed large B-cell lymphoma. These cell lines were CD3, CD18, CD20, and CD90 positive with variable CD79a, CD1c and CD34 expression. All cell lines were tumorigenic in Nu/nu mice and were wild type for p53. Canine lymphoma cell lines serve as an important resource for translational lymphoma research.
Identification of Candidate B-Lymphoma Genes by Cross-Species Gene Expression Profiling
PLoS ONE, 2013
Comparative genome-wide expression profiling of malignant tumor counterparts across the human-mouse species barrier has a successful track record as a gene discovery tool in liver, breast, lung, prostate and other cancers, but has been largely neglected in studies on neoplasms of mature B-lymphocytes such as diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We used global gene expression profiles of DLBCL-like tumors that arose spontaneously in Myc-transgenic C57BL/6 mice as a phylogenetically conserved filter for analyzing the human DLBCL transcriptome. The human and mouse lymphomas were found to have 60 concordantly deregulated genes in common, including 8 genes that Cox hazard regression analysis associated with overall survival in a published landmark dataset of DLBCL. Genetic network analysis of the 60 genes followed by biological validation studies indicate FOXM1 as a candidate DLBCL and BL gene, supporting a number of studies contending that FOXM1 is a therapeutic target in mature B cell tumors. Our findings demonstrate the value of the "mouse filter" for genomic studies of human B-lineage neoplasms for which a vast knowledge base already exists.
Hematological Oncology, 2015
Background and Aim: There are over 400 genetically distinct breeds of dogs, each corresponding to a genetic isolate. The consequence of breeding practices is that most breeds naturally develop specific cancer types, reflecting the presence of predisposing alleles. This is interesting for lymphomas, as most human lymphoma subtypes are encountered in dogs, with some subtypes over-represented in specific breeds (Pastor et al., 2009; Rowell et al., 2011; Marconato et al., 2013). We focused on lymphoma occurring in large families of Bernese Mountain Dogs (BMDs) with the objectives to identify predisposing genetic regions and somatic alterations involved in lymphomagenesis. Materials and Methods: We collected blood and tumour samples, clinical and genealogical information of affected BMDs, using the French CaniDNA biobank at CNRS, Rennes. Histopathological diagnosis was performed from formalin-fixed paraffin-embedded tumour samples by veterinary pathologists F. N. and J. A. DNA and RNA we...
PLoS ONE, 2014
Canine Diffuse Large B-cell Lymphoma (cDLBCL) is an aggressive cancer with variable clinical response. Despite recent attempts by gene expression profiling to identify the dog as a potential animal model for human DLBCL, this tumor remains biologically heterogeneous with no prognostic biomarkers to predict prognosis. The aim of this work was to identify copy number aberrations (CNAs) by high-resolution array comparative genomic hybridization (aCGH) in 12 dogs with newly diagnosed DLBCL. In a subset of these dogs, the genetic profiles at the end of therapy and at relapse were also assessed. In primary DLBCLs, 90 different genomic imbalances were counted, consisting of 46 gains and 44 losses. Two gains in chr13 were significantly correlated with clinical stage. In addition, specific regions of gains and losses were significantly associated to duration of remission. In primary DLBCLs, individual variability was found, however 14 recurrent CNAs (.30%) were identified. Losses involving IGK, IGL and IGH were always found, and gains along the length of chr13 and chr31 were often observed (.41%). In these segments, MYC, LDHB, HSF1, KIT and PDGFRa are annotated. At the end of therapy, dogs in remission showed four new CNAs, whereas three new CNAs were observed in dogs at relapse compared with the previous profiles. One ex novo CNA, involving TCR, was present in dogs in remission after therapy, possibly induced by the autologous vaccine. Overall, aCGH identified small CNAs associated with outcome, which, along with future expression studies, may reveal target genes relevant to cDLBCL.