Repository logo
 

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

Published version
Peer-reviewed

Type

Article

Change log

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

Journal Title

Nature communications

Conference Name

Journal ISSN

2041-1723

Volume Title

11

Publisher

Sponsorship
NIDDK NIH HHS (R24 DK106766)