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The Skorski lab focuses on the determination of the role of DNA repair mechanisms in acute (AML) and chronic (CML) leukemias, including the potential of therapeutic interventions. We found that acute and chronic leukemia stem cells (LSCs) accumulate potentially lethal DNA double strand breaks (DSBs), but homologous recombination (HR) and nonhomologous endjoining (NHEJ) protect their survival. Normal cells use BRCA1/2-dependent HR and DNAPK –mediated NHEJ to prevent DSB-triggered apoptosis. However, leukemia cells may employ RAD52-mediated HR and PARP1mediated NHEJ. These changes may be driven by genetic and epigenetic aberrations. Individual patients with leukemias displaying deficiencies in specific DSB repair pathways are identified by Gene Expression and Mutation Analysis (GEMA). We explore these differences to target tumorspecific DNA repair mechanisms to achieve “synthetic lethality” in leukemia cells, with negligible effects on normal cells. These studies will lead to novel therapeutic approaches based on the induction of personalized medicineguided synthetic lethality in leukemias from individual patients. We were first to demonstrate that targeting RAD52 can be successfully applied in individual leukemias identified by GEMA.
The Skorski lab focuses on the determination of the role of DNA repair mechanisms in acute (AML) and chronic (CML) leukemias, including the potential of therapeutic interventions. We found that acute and chronic leukemia stem cells (LSCs) accumulate potentially lethal DNA double strand breaks (DSBs), but homologous recombination (HR) and nonhomologous endjoining (NHEJ) protect their survival. Normal cells use BRCA1/2-dependent HR and DNAPK –mediated NHEJ to prevent DSB-triggered apoptosis. However, leukemia cells may employ RAD52-mediated HR and PARP1mediated NHEJ. These changes may be driven by genetic and epigenetic aberrations. Individual patients with leukemias displaying deficiencies in specific DSB repair pathways are identified by Gene Expression and Mutation Analysis (GEMA). We explore these differences to target tumorspecific DNA repair mechanisms to achieve “synthetic lethality” in leukemia cells, with negligible effects on normal cells. These studies will lead to novel therapeutic approaches based on the induction of personalized medicineguided synthetic lethality in leukemias from individual patients. We were first to demonstrate that targeting RAD52 can be successfully applied in individual leukemias identified by GEMA.
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