Elucidating the contribution of AID to the clonal evolution of CLL

The activation induced cytidine deaminase (AID) is specifically expressed in germinal centre B cells where it is required for both somatic hypermutation and class switch recombination of the immunoglobulin (Ig) genes by directly deaminating cytosines to uracils. As AID causes a substantial amount of off-target mutations, its activity has been associated with lymphomagenesis and clonal evolution of B cell malignancies. In Chronic lymphocytic leukemia (CLL), the leukemic B cells share a clonal B cell receptor consisting of specifically rearranged VDJ heavy and VJ light chain genes. In our preliminary experiments, we could show a substantial subclonal diversity at VDJ as well as at IgM switch (S) regions, showing ongoing AID on-target activity in vivo during disease progression. In parallel, we could show that in a CLL mouse model, AID is required for the development of a more aggressive, transplantable CLL clone. Our preliminary data strongly support the involvement of AID in clonal evolution of CLL. In this project, we hence aim at elucidating how AID contributes to clonal evolution of CLL, which genomic targets are hit by AID and whether AID inhibition might improve treatment outcome in CLL.

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