Nanoparticle-mediated targeting of the fusion gene RUNX1/ETO in t(8;21)-positive acute myeloid leukaemia.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
21
10
2022
accepted:
14
02
2023
revised:
10
02
2023
medline:
10
4
2023
pubmed:
25
2
2023
entrez:
24
2
2023
Statut:
ppublish
Résumé
A hallmark of acute myeloid leukaemias (AMLs) are chromosomal rearrangements that give rise to novel leukaemia-specific fusion genes. Most of these fusion genes are both initiating and driving events in AML and therefore constitute ideal therapeutic targets but are challenging to target by conventional drug development. siRNAs are frequently used for the specific suppression of fusion gene expression but require special formulations for efficient in vivo delivery. Here we describe the use of siRNA-loaded lipid nanoparticles for the specific therapeutic targeting of the leukaemic fusion gene RUNX1/ETO. Transient knockdown of RUNX1/ETO reduces its binding to its target genes and alters the binding of RUNX1 and its co-factor CBFβ. Transcriptomic changes in vivo were associated with substantially increased median survival of a t(8;21)-AML mouse model. Importantly, transient knockdown in vivo causes long-lasting inhibition of leukaemic proliferation and clonogenicity, induction of myeloid differentiation and a markedly impaired re-engraftment potential in vivo. These data strongly suggest that temporary inhibition of RUNX1/ETO results in long-term restriction of leukaemic self-renewal. Our results provide proof for the feasibility of targeting RUNX1/ETO in a pre-clinical setting and support the further development of siRNA-LNPs for the treatment of fusion gene-driven malignancies.
Identifiants
pubmed: 36823395
doi: 10.1038/s41375-023-01854-8
pii: 10.1038/s41375-023-01854-8
pmc: PMC10079536
doi:
Substances chimiques
Core Binding Factor Alpha 2 Subunit
0
Oncogene Proteins, Fusion
0
RNA, Small Interfering
0
Runx1 protein, mouse
0
RUNX1 Translocation Partner 1 Protein
0
RUNX1T1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
820-834Subventions
Organisme : Cancer Research UK
ID : C27943/A23389
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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