Dissecting the early steps of MLL induced leukaemogenic transformation using a new mouse model of AML [ATAC-seq]

Leukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the intricate regulatory programs that control multi-lineage differentiation and self-renewal in haematopoietic stem and progenitor cells. Translocations involving the Mll1 gene generate particularly powerful oncogenic fusion proteins, predominantly affecting infant and paediatric AML and ALL patients. The early stages of leukaemogenic transformation are typically inaccessible from human patient samples, and are not captured by conventional mouse models. Here, we took advantage of conditionally immortalised multipotent haematopoietic progenitor cells to develop a new MLL-r model capturing the early cellular and molecular consequences of MLL-ENL expression based on a clear clonal relationship between the parental and MLL-leukaemic cells. Through a combination of scRNA-seq, ATAC-seq and genome-scale CRISPR-Cas9 screening, we identified pathways and genes likely to be important during the early phases of leukaemogenesis. Finally, we demonstrate the broad utility of using matched parental and transformed cells for small molecule inhibitor studies by validating both known and new potential therapeutic targets. ATAC-Seq of parental and MLLENL transformed Hoxb8 cells