Objectif
Lymphoid cancers are among the most common human malignancies and characteristically harbour genomic aberrations. Although databases will soon be flooded with genome sequences from thousands of tumours, interpretation and validation of these data is limited by the genetic variability and uncontrolled environmental exposures inherent to human studies. There is therefore a growing need in complementary approaches that would provide understanding of how and which genomic aberrations underlie tumour genesis. It has become apparent that the generation of DNA double strand breaks during the process of antigen receptor diversification, including RAG1/2 protein-generated DNA breaks during V(D)J recombination, are key intermediates in the appearance of lymphoid neoplasm. In this project, we propose to elucidate the molecular mechanisms, the genomic lesions and the oncogenic pathways underlying B and T cell cancers using a combination of mouse models and cutting-edge cytogenetic, genomic and transcriptomic technologies. We aim (i) to define the major genomic lesions and oncogenic pathways underlying the rapid onset of T-cell lymphomas in a unique mouse model that carries exacerbated RAG-induced genomic instability; (ii) to decipher the genomic lesions and pathways underlying B versus T lymphoma tropism; (iii) to investigate the functional interactions between RAG- and DNA damage response / DNA repair-complexes in suppressing genomic instability and lymphomagenesis; and (iv) to identify and validate lesions and genes underlying human B and T cell cancers using a cross-species oncogenomic comparative approach. In doing so, this study will also 1) increase our understanding of the fundamental mechanisms maintaining genome stability during lymphocyte development; 2) greatly improve interpretation and validation of whole genome sequencing analysis of human leukaemia and lymphoma; and 3) provide well-characterized animal models for developing and testing targeted therapeutics.
Champ scientifique
Appel à propositions
ERC-2012-StG_20111109
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Régime de financement
ERC-SG - ERC Starting GrantInstitution d’accueil
75724 Paris
France