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

Accepted version
Peer-reviewed

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Authors

Basilico, Silvia 
Tzelepis, Konstantinos  ORCID logo  https://orcid.org/0000-0002-4865-7648
Giotopoulos, George  ORCID logo  https://orcid.org/0000-0003-1390-6592

Abstract

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.

Description

Keywords

Animals, Cell Transformation, Neoplastic, DNA-Binding Proteins, Disease Models, Animal, Female, Hematopoietic Stem Cells, Histone-Lysine N-Methyltransferase, Homeodomain Proteins, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Inbred C57BL, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Transcription Factors

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

11

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Leukaemia & Lymphoma Research (12029)
Cancer Research UK (21762)
Wellcome Trust (206328/Z/17/Z)
National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (CRUK-A19405)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/M008975/1)
Wellcome Trust (210926/Z/18/Z)
Medical Research Council (2494415)
CRUK, Wellcome Trust, Bloodwise, MRC, NIH