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While chronic lymphocytic leukemia (CLL) typically shows only delayed progression, various genomic aberrations that are associated with rapid transformation and poor therapy response, have been identified. Specifically, del(17p) affecting TP53 and del(11q), affecting ATM and others, such as SF3B1 are associated with an adverse prognosis. Based on these observations and the dramatic clinical need for an improvement of our therapeutic options for ATM- or TP53-deficient CLLs, we generated novel, autochthonous mouse models of CLL that faithfully mimic this group of high risk CLLs. We have employed single and dual recombinase strategies to mimic the process of clonal evolution in vivo, and we are employing reporter alleles to longitudinally follow the fate of individual CLL clones, in vivo. We are now using our novel genetically engineered CLL mouse models as a preclinical platform, which allows the rapid validation of hypotheses generated in our in vitro functional genomics screening platform.