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Modeling lymphoma pathogenesis in mice - from basic mechanisms to pre-clinical models

Objective

Human B cell lymphomas including multiple myeloma and Hodgkin¿s disease are frequent malignancies and a major clinical problem. Their high incidence is due to special features of normal B cell development that promote chromosomal translocations and other genetic alterations. Another contributing factor is Epstein-Barr-Virus (EBV), a B cell-transforming virus endemic in humans. EBV-infected cells are usually eliminated by the immune system, but in immunosuppressed (post-transplant or AIDS) patients, EBV infection spreads and drives lymphomagenesis.
We have generated a novel genetic tool that allows us to introduce combinations of loss- and gain-of-function mutations specifically into B cells in the mouse, to analyze the cooperation of oncogenic factors thought to contribute to B lymphomagenesis in humans. The unique feature of this method is that only a small fraction of cells is mutated (mimicking the sporadic nature of somatic cancerogenesis) and that cells having acquired either single or combined mutations can be observed side-by-side.
Using a large set of mutant alleles, we will test whether the interplay of certain combinations of survival, proliferation and differentiation signals determines the development of different classes of human B cell malignancies. A special focus is on Hodgkin¿s disease, where EBV infection and genetic reprogramming play a critical role. We will also investigate the mechanism of immune surveillance of EBV-infected B cells and EBV-driven B cell lymphomas.
Ultimately we hope to elucidate key pathways of lymphoma pathogenesis, identify novel contributing mutations, and generate preclinical mouse models to assess therapeutic strategies and mechanisms of tumor immune surveillance.

Call for proposal

ERC-2010-AdG_20100317
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Host institution

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Address
Robert Rossle Strasse 10
13125 Berlin
Germany
Activity type
Research Organisations
EU contribution
€ 2 487 787
Principal investigator
Peter Klaus Georg Rajewsky (Prof.)
Administrative Contact
Ioannis Legouras (Dr.)

Beneficiaries (1)

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Germany
EU contribution
€ 2 487 787
Address
Robert Rossle Strasse 10
13125 Berlin
Activity type
Research Organisations
Principal investigator
Peter Klaus Georg Rajewsky (Prof.)
Administrative Contact
Ioannis Legouras (Dr.)