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

Silvia Basilico, Xiaonan Wang, Alison Kennedy, Konstantinos Tzelepis, George Giotopoulos, Sarah J. Kinston, Pedro M. Quiros, Kim Wong, David J. Adams, Larissa S. Carnevalli, Brian J. P. Huntly, George S. Vassiliou, Fernando J. Calero-Nieto () and Berthold Göttgens ()
Additional contact information
Silvia Basilico: Jeffrey Cheah Biomedical Centre
Xiaonan Wang: Jeffrey Cheah Biomedical Centre
Alison Kennedy: Jeffrey Cheah Biomedical Centre
Konstantinos Tzelepis: Wellcome Trust Sanger Institute
George Giotopoulos: Jeffrey Cheah Biomedical Centre
Sarah J. Kinston: Jeffrey Cheah Biomedical Centre
Pedro M. Quiros: Wellcome Trust Sanger Institute
Kim Wong: Wellcome Trust Sanger Institute
David J. Adams: Wellcome Trust Sanger Institute
Larissa S. Carnevalli: AstraZeneca
Brian J. P. Huntly: Jeffrey Cheah Biomedical Centre
George S. Vassiliou: Jeffrey Cheah Biomedical Centre
Fernando J. Calero-Nieto: Jeffrey Cheah Biomedical Centre
Berthold Göttgens: Jeffrey Cheah Biomedical Centre

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-15220-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15220-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-15220-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().