B10 (New): Genetic and epigenetic charaterization of chronic lymphocytic leukemia with translocations involving the immunoglobulin loci

Translocations involving IG loci are present in approximately 10% of CLL. Although the biological and prognostic impact of IG aberrations and respective translocation partner genes remain yet largely unclear, such IG rearrangements putatively indicate a poor prognosis and may define distinct disease entities. None of the published large genomic and epigenomic studies on CLL contained a considerable number of IG-translocated CLLs. In a start-up project funded by CRC 1074, we characterized more than 200 IG-translocated CLL and are further profiling cases with BCL3 and MYC as partners. We hypothesize that a comprehensive characterization of IG-translocated CLL might provide important insights in the pathogenesis, classification and clinical course of this disease. We propose four specific aims: 1) identification of novel IG translocation partner genes and thereby potential oncogenes in CLL; 2) comprehensive description of the genetic landscape and epigenetic patterns in IG-translocated CLL; 3) functional characterization of BCL3/PVRL2- and other putative high-impact IG partners in CLL; 4) evaluation of the impact of IG-rearrangements on disease evolution, clinical progression and response to targeted therapies. The genomic, epigenomic, functional, and clinical characterization of IG-translocated CLLs will not only enhance our understanding of the biology and classification of the disease, but will also yield new insights into deregulated pathways potentially providing cellular targets for novel therapies.

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