A synthetic lethal screen to identify novel targets for therapy in acute myeloid leukemia

• Applicant: Professor Dr. Andreas Neubauer
• Subject Area: Hematology, Oncology
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 59021035

Acute myeloid leukemia (AML) is a model disease in cancer research. As in other cancer types, most AML patients still die of their disease, most frequently because of drug resistance. In our previous work we have shown that oncogenic RAS modulates drug sensitivity by interacting with a DNA-damage program that is p53 dependent and causes cellular differentiation, thereby leading to decrease of immature leukemia stem cells and significant less relapses. Our project intended to study drug resistance in cancer cells by using a synthetic lethal screen with cytarabine and daunorubicine (drugs that are frequently used in the therapy of AML). We took advantage of a DNA-repair siRNA library, as drug resistance frequently is caused by a change in DNArepair. To this end, we have used a siRNA screening consisting of 437 siRNA probes specific for DNA-repair genes and applied this to U2OS osteosarcoma cells (as proposed, because expression of siRNA libraries into AML cells is rather difficult). So far, we have identified several candidate genes, which sensitize cells to cytarabine-treatment when knocked-down. Some of these genes have been implicated in drug resistance, and some are also “druggable”. Currently, we are validating these candidate genes. We now want to analyze genes in human primary AML samples and correlate these data with clinical parameters. Our goal therefore is to overcome drug resistance in AML. Ultimately, these data may lead to a more individualized AML therapy, resulting in better treatment outcome.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 210: Genetics of Drug Resistance in Cancer