A9: Role of B cell receptor signaling and acquired immunoglobulin gene changes in the development of chronic lymphocytic leukemia (CLL)

CLL is a frequent lymphoproliferative disorder of mature B cells. In the previous funding period, we found that the B cell antigen receptor (BCR) is pivotal for the maintenance of CLL cells and that autonomous BCR signaling and augmented phosphatidylinositol-3 kinase (PI3K) activity as well as a block in terminal differentiation support CLL development. In the next funding period, we aim at characterizing signaling proteins as potential novel targets for CLL treatment. We will investigate the role of the small GTPase RhoA in the survival of B cells and will test whether RhoA might serve as a target for CLL treatment. Furthermore, we will establish an in vitro reconstitution system using splenic cells from TCL1-transgenic mice to study the structure-function relationship of CLL-derived BCRs. Additionally, we will generate animal models carrying CLL-derived BCRs using pre-rearranged Ig chains containing the R110 mutation to study the role of R110 mutation and respective light chain in CLL pathogenesis.

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