Abstract: This project aims to technologically refine and set new standards for genome-wide cancer gene discovery through forward genetic screening by leveraging the power of single-cell methods. This approach will massively reduce the number of experimental animals and resources required for future in vivo screenings and maximize the method's robustness in line with the 3R principles. The concrete animal experiment is a PiggyBac transposon mutagenesis screen in a mouse model of ASXL1-mutated

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... ute myeloid leukemia (AML), a disease characterized by a dismal prognosis and a significant unmet medical need. The screen will identify unknown driver genes and signaling pathways to better the understanding of the complex ASXL1-mutated AML tumor biology and of in vivo clonal evolution with subsequent clinical translation, e.g. by developing mechanism-based therapies. We will evaluate whether a screen using genome and transcriptome single-cell sequencing applied to micro cohorts of mice can replace an established pipeline for cancer gene discovery using bulk methods that require a considerably larger number of samples due to limited resolution.