Dissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML

• DOI: 10.1038/s41467-020-15220-0
• Publication Date: 2020-03-16T11:05:42Z
• Authors: Silvia Basilico; Xiaonan Wang; Alison Kennedy; Konstantinos Tzel...; George Giotopoulos; Sarah J. Kinston; Pedro M. Quiros; Kim Wong; David J. Adams; Larissa S. Carnev...; Brian J. P. Huntly; George S. Vassiliou; Fernando J. Caler...; Berthold Göttgens
• Keywords: Oncogene Proteins, Fusion; Science; Article; /38/91; Mice; /42/47; /38/23; /631/208/4041; /38/22; Animals; Humans; Homeodomain Proteins; Q; article; Histone-Lysine N-Methyltransferase; Hematopoietic Stem Cells; /96/21; /631/1647/514/2254; 3. Good health; DNA-Binding Proteins; Mice, Inbred C57BL; /13/31; Disease Models, Animal; Leukemia, Myeloid, Acute; Cell Transformation, Neoplastic; /631/67/1990/283/1897; Female; /38/39; /64/60; Myeloid-Lymphoid Leukemia Protein; Transcription Factors

AbstractLeukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the regulatory programs that control self-renewal and differentiation of stem and progenitor cells. Translocations involving theMll1(Kmt2a) gene generate powerful oncogenic fusion proteins, predominantly affecting infant and paediatric AML and ALL patients. The early stages of leukaemogenic transformation are typically inaccessible from human patients and conventional mouse models. Here, we take advantage of cells conditionally blocked at the multipotent haematopoietic progenitor stage to develop a MLL-r model capturing early cellular and molecular consequences of MLL-ENL expression based on a clear clonal relationship between parental and leukaemic cells. Through a combination of scRNA-seq, ATAC-seq and genome-scale CRISPR-Cas9 screening, we identify pathways and genes likely to drive 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 previously known and other potential therapeutic targets.