Classical Hodgkin's disease (HD) is the most common lymphoma in the Western World. The malignant cells in HD are the so-called Hodgkin and Reed-Sternberg (HRS) cells, which comprise only a few percent or less of the lymphoma tissue. In roughly half of the patients, the HRS cells are infected with Epstein-Barr-Virus (EBV) and express the EBV-encoded membrane proteins LMP1 and LMP2A. These proteins are constitutively active and in B cells partially mimic signals of the CD40 co-receptor and the antigen receptor (BCR), respectively. Based on these circumstances and on our own molecular analysis of Ig gene rearrangements in micro manipulated HRS cells we have developed a scenario of HD pathogenesis. In this scenario, HRS cells derive in most instances from pre-apoptotic germinal center (GC) B cells rescued by some transforming event(s). In EBV+ HD, LMP1 and LMP2A may participate in this initial rescue.
The aim of this proposal is to reconstruct this scenario in the mouse by conditional gene targeting techniques. We have developed a mouse mutant in which Cre recombinase is efficiently expressed in GC but not naive B cells. This will be used to target expression of LMP2A and/or LMP1 to GC B cells in vivo. The interference of the viral proteins with the GC reaction will be investigated. Rescue of pre-apoptotic GC B cells that have lost BCR expression because of somatic hypermutation might be observed, as well as lymphomagenesis, given the known oncogenic properties of LMP1. These experiments will be complemented by an attempt to target another potential tumor determinant of HRS cells into GC B cells, namely the activated form of Notch1. This molecule has recently been shown to be expressed in HRS cells at high levels and in an activated form. Notch1 is particularly attractive in this context, because it is involved in lineage decisions in lymphocyte progenitors, promoting T cell development. Curiously, HRS cells have down regulated many B cell-specific genes and express molecular markers of other hematopoietic lineages, including T cells. Notch1, which is also a potent oncogene if ectopically expressed, might thus contribute to this curious phenotype as well as to HRS cell transformation. Combining LMP2A, LMP1 and Notch1 expression in GC B cells by conditional gene targeting might lead to a mouse model of HD. Apart from lymphomagenesis, the proposed experiments should also lead to new insights into the biology of the GC reaction in the context of EBV infection.
|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|
|Zhang, Baochun; Calado, Dinis Pedro; Wang, Zhe et al. (2015) An oncogenic role for alternative NF-?B signaling in DLBCL revealed upon deregulated BCL6 expression. Cell Rep 11:715-26|
|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|
|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|
|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|
|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|
|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; 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|
|Casola, Stefano; Otipoby, Kevin L; Alimzhanov, Marat et al. (2004) B cell receptor signal strength determines B cell fate. Nat Immunol 5:317-27|