Journal Article

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

Adams, David J., Vassiliou, George S., Carnevalli, Larissa S., Huntly, Brian J. P., Wang, Xiaonan, Tzelepis, Konstantinos, Göttgens, Berthold, Basilico, Silvia, Giotopoulos, George, Calero-Nieto, Fernando J., Wong, Kim, Kinston, Sarah J., Quiros, Pedro M., Kennedy, Alison

2020

Overview

Leukaemogenic 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 the Mll1 ( 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. The oncogene MLL is frequently translocated in leukemia, resulting in oncogenic fusion proteins. Here, the authors report a temporally controlled mouse model of MLL-ENL driven leukemia AND identify therapeutic targets associated with early MLL-ENL driven leukaemogenesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 38/22 / 38/23 / 38/39 / 38/91 / 42/47 / 631/1647/514/2254 / 631/208/4041 / 631/67/1990/283/1897 / 64/60 / 96/21 / Acute myeloid leukemia / Animal models / Animals / Cell differentiation / Cell self-renewal / Cell Transformation, Neoplastic / Cells (biology) / CRISPR / Differentiation (biology) / Disease Models, Animal / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Female / Genetic transformation / Genomes / Hematopoietic stem cells / Hematopoietic Stem Cells - metabolism / Histone-Lysine N-Methyltransferase - genetics / Histone-Lysine N-Methyltransferase - metabolism / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humanities and Social Sciences / Humans / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - physiopathology / Mice / Mice, Inbred C57BL / MLL protein / multidisciplinary / Mutation / Myeloid-Lymphoid Leukemia Protein - genetics / Myeloid-Lymphoid Leukemia Protein - metabolism / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Progenitor cells / Proteins / Science / Science (multidisciplinary) / Stem cells / Target recognition / Therapeutic applications / Transcription Factors - genetics / Transcription Factors - metabolism / Transformed cells / Translocation