Chronic lymphocytic leukemia (CLL) has become increasingly accessible for therapeutic approaches, particularly by targeting the B-cell receptor signaling and through the usage of monoclonal antibodies. However, treatment refractory disease and progression towards aggressive Lymphoma such as Richter´s transformation remains a major obstacle in current patient care. We have recently established a murine model of transformation from CLL towards aggressive lymphoma phenotype by the introduction of constitutively active AKT-signaling in the well-established Eµ-TCL1 mouse model. We observed decreased survival and a high-grade-lymphoma phenotype in our new Eµ-TCL1/CD19-Cre/cAKT (TCA) model of Richter´s syndrome and will now approach to analyze the functional implication of constitutively active AKT signaling upon CLL progression as the therapeutic consequences and potential approaches towards transformed CLL. First, we will in particular investigate the impact of prolonged constitutively active AKT on acquisition of auxillary DNA damage and driving mutations. Furthermore we will analyze in a time-dependent manner the epigenetic changes induced by in the TCA-model under transformation of the CLL B-cell. Second, we will analyze the down-stream consequences of constitutively active AKT. Here we will analyze the impact on p53 degradation, regulation of FOXO1 dependent transcription and further downstream signaling through GSK3beta.
Third we will employ the TCA mouse model of Richter´s transformation in CLL for therapeutic modeling. Here we will be able to apply principles of synergy identified in the first funding period and am towards identifying potential novel combinatorial approaches against Richter´s syndrome.