In Hodgkin's Disease (HD), the most common lymphoma in the Western world, the malignant cells are the so-called Hodgkin and Reed-Sternberg (HRS) cells, comprising only a few percent of the lymphoma mass. HRS cells are often infected by Epstein-Barr-Virus (EBV) and express the EBV proteins LMP1 and LMP2A, partially mimicking constitutively an active CD40 co-receptor and B cell antigen receptor (BCR), respectively. Previous work, which had identified somatically mutated B cells, often bearing mutations "crippling" BCR expression, as HRS progenitors, led to a scenario of HD pathogenesis, in which HRS cells derive from pre-apoptotic GC B cells rescued by LMP2A and LMP1 expression. Despite their B cell origin, HRS cells have largely lost the B cell-specific gene expression program and acquired expression of genes typical for the T and/or myeloid hematopoietic lineages. We hypothesize that this lineage infidelity is dictated by the interference of certain transcription factors (TFs) known to be expressed in HRS cells, namely Id2, ABF1 and Notch1, with the B cell- specific gene expression program. This together with constitutive expression of proteins promoting cell survival and proliferation, like the TF c-Jun and TFs of the NF-kB family, may ultimately reprogram GC B cells into HRS cells. In this general scenario, EBV infection is a major initial transforming event in HD, and is indeed known to result in up-regulation of the TFs NF-kB, AP1, Id2 and ABF1 in B cells. Following this general hypothesis, we have developed a strategy to target the expression of candidate genes into GC B cells, using Cre-mediated conditional gene targeting. Using and further improving these tools, we plan to analyze whether induced expression of the various EBV-derived proteins and TFs individually and in combination in GC B cells will result in trans-differentiation and transformation of those cells as it is seen in HRS cells in HD. Our ultimate goal is to generate a mouse model of HD and to better understand the role of cellular reprogramming in lymphomagenesis. A second EBV-associated disease addressed in the present proposal is Post-Transplant Lymphoproliferative Disorder (PTLD), common in post-transplantation patients and due to a significant extent to the outgrowth of EBV-infected B cells because of immune suppression. We have found that induced expression of the EBV protein LMP1, known to be a major player in EBV-mediated B cell transformation, in developing B cells in the mouse leads to the rejection of these cells by the immune system. Depletion of T cells in the animals results in the rapid outgrowth of LMP1 expressing B cell blasts and death of the mice within a few weeks. We plan to develop this system into a first mouse model of PTLD, by targeting LMP1 expression into mature B cells, and to fully characterize disease progression and reversibility in the mutant animals, with a view of ultimately using this model for the development of new therapeutic strategies. Public Health Relevance: Hodgkin's Disease (HD) is the most common lymphoma in the Western world, and Post-Transplant Lymphoproliferative Disorder (PTLD) is an important cause of morbidity and mortality in post-transplantation patients, posing a significant clinical problem. Epstein-Barr-Virus (EBV) plays a major role in both HD and PTLD, with almost half of the HD cases and most of PTLDs being associated with it. The present proposal is based on known features of the pathogenesis of these diseases in the human and extensive own work, and aims at the generation of EBV-related mouse models of HD and PTLD, which so far do not exist, but should open the way to new therapeutic strategies and also shed new light on the role of gene expression reprogramming in lymphomagenesis.
Hodgkin's Disease (HD) is the most common lymphoma in the Western world, and Post-Transplant Lymphoproliferative Disorder (PTLD) is an important cause of morbidity and mortality in post-transplantation patients, posing a significant clinical problem. Epstein-Barr-Virus (EBV) plays a major role in both HD and PTLD, with almost half of the HD cases and most of PTLDs being associated with it. The present proposal is based on known features of the pathogenesis of these diseases in the human and extensive own work, and aims at the generation of EBV-related mouse models of HD and PTLD, which so far do not exist, but should open the way to new therapeutic strategies and also shed new light on the role of gene expression reprogramming in lymphomagenesis.
|Zhang, Baochun; Calado, Dinis Pedro; Wang, Zhe et al. (2015) An oncogenic role for alternative NF-ÎºB signaling in DLBCL revealed upon deregulated BCL6 expression. Cell Rep 11:715-26|
|Ba, Zhaoqing; Meng, Fei-Long; Gostissa, Monica et al. (2015) A Rapid Embryonic Stem Cell-Based Mouse Model for B-cell Lymphomas Driven by Epstein-Barr Virus Protein LMP1. Cancer Immunol Res 3:641-9|
|Gostissa, Monica; Schwer, Bjoern; Chang, Amelia et al. (2014) IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances. Proc Natl Acad Sci U S A 111:2644-9|
|Delahanty, Ryan J; Xiang, Yong-Bing; Spurdle, Amanda et al. (2013) Polymorphisms in inflammation pathway genes and endometrial cancer risk. Cancer Epidemiol Biomarkers Prev 22:216-23|
|Gostissa, Monica; Bianco, Julia M; Malkin, Daniel J et al. (2013) Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center-derived B-cell lymphomas. Proc Natl Acad Sci U S A 110:2934-9|
|Zhang, Baochun; Kracker, Sven; Yasuda, Tomoharu et al. (2012) Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model. Cell 148:739-51|
|Rajewsky, Klaus; von Boehmer, Harald (2008) Lymphocyte development: overview. Curr Opin Immunol 20:127-30|
|Casola, Stefano; Cattoretti, Giorgio; Uyttersprot, Nathalie et al. (2006) Tracking germinal center B cells expressing germ-line immunoglobulin gamma1 transcripts by conditional gene targeting. Proc Natl Acad Sci U S A 103:7396-401|
|Klein, Ulf; Casola, Stefano; Cattoretti, Giorgio et al. (2006) Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol 7:773-82|
|Casola, Stefano; Otipoby, Kevin L; Alimzhanov, Marat et al. (2004) B cell receptor signal strength determines B cell fate. Nat Immunol 5:317-27|