Using a conditional KrasG12D knock-in mouse model, we and others have demonstrated that expression of oncogenic Kras in hematopoietic progenitor cells causes an arrest at the DN2/3 stage during T-cell differentiation followed by the development of an aggressive T-cell lymphoblastic leukemia/lymphoma with long disease latency. Interestingly, 50% of analysed leukemia samples harboured Notch1-mutations, likely acquired during the KrasG12D-mediated block in differentiation. These additional mutations may be acquired by replicative stress or increased reactive oxygen species (ROS) production. Alternatively, oncogenic RAS may directly affect DNA repair pathways, thereby causing misrepair and, due to concomitant resistance to apoptotic cell death, accumulation of genomic changes. In line with this hypothesis, recent studies indicated that DNA damage response and repair (DDR) can be disturbed within a defined malignant background. Using several in vitro and in vivo models, we analyse DNA repair pathways in KRASMUT and KRASWT cells. Upon induction of DNA double strand breaks, expression of oncogenic KRAS was associated with a shift to the preferential use of the error-prone alternative non-homologous end-joining (alt-NHEJ) pathway.
Interestingly, targeting components of this pathway significantly enhanced chemotherapy-induced apoptotic cell death. Of note, this effect was specific for leukemic cell harbouring KRAS-mutations. Currently, we systematically explore DNA damage repair pathways in the context of distinct oncogenes in several leukemia models and solid tumors.