Recurrent oncogenic chromosomal rearrangements are a hallmark of lymphoid malignancies and are considered to be the driving force in tumor survival and progression. While oncogenes typically induce uncontrolled proliferation, they also induce metabolic stress and constitutive DNA damage. Hence, at the time of diagnosis tumor genomes are typically highly mutated. Not surprisingly, forced expression of an oncogene in healthy cells results in oncogenic stress leading to apoptosis or cell cycle arrest. This phenomenon is considered as an initial cellular barrier to prevent malignancy. However, tumor cells did pass this barrier, and it is assumed that they did so by acquisition of additional defects that allow them to tolerate oncogene expression. Oncogene-induced DNA damage is likely to initiate these transforming genomic defects and may further contribute to tumor progression. The proposed study is designed to address this subject. The goals of the proposed study are a) to identify and functionally characterize oncogene-induced DNA damage in a genome-wide manner and b) to uncover resulting genomic lesions that mediate tolerance to oncogenic stress and are required for initiation of malignancy. The proposed work will lead to a better understanding of tumor development and opens the opportunity for the development of new treatment strategies for human leukemia and lymphoma based on reactivation of oncogene-induced lethality in cancer cells.