Harnessing the MYB-dependent TAL1 5'super-enhancer for targeted therapy in T-ALL.
Cancer
Oncogene
Super-enhancer
Targeted therapy
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
18 01 2023
18 01 2023
Historique:
received:
21
11
2022
accepted:
16
12
2022
entrez:
17
1
2023
pubmed:
18
1
2023
medline:
20
1
2023
Statut:
epublish
Résumé
The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation mechanisms, yet how each mechanism impacts clinical outcome is unclear. Using T-cell acute lymphoblastic leukemia (T-ALL) as an example, we show that patients harboring 5'super-enhancer (5'SE) mutations of the TAL1 oncogene identifies a specific patient subgroup with poor prognosis irrespective of the level of oncogene dysregulation. Remarkably, the MYB dependent oncogenic 5'SE can be targeted using Mebendazole to induce MYB protein degradation and T-ALL cell death. Of note Mebendazole treatment demonstrated efficacy in vivo in T-ALL preclinical models. Our work provides proof of concept that within a specific oncogene driven cancer, the mechanism of oncogene dysregulation rather than the oncogene itself can identify clinically distinct patient subgroups and pave the way for future super-enhancer targeting therapy.
Identifiants
pubmed: 36650499
doi: 10.1186/s12943-022-01701-x
pii: 10.1186/s12943-022-01701-x
pmc: PMC9847025
doi:
Substances chimiques
Proto-Oncogene Proteins
0
T-Cell Acute Lymphocytic Leukemia Protein 1
0
Basic Helix-Loop-Helix Transcription Factors
0
Mebendazole
81G6I5V05I
TAL1 protein, human
135471-20-4
Types de publication
Letter
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12Informations de copyright
© 2023. The Author(s).
Références
Blood. 2017 Jun 15;129(24):3264-3268
pubmed: 28408461
Leukemia. 2018 Apr;32(4):882-889
pubmed: 29089643
Cancer Cell. 2002 Feb;1(1):75-87
pubmed: 12086890
Blood. 2005 Jul 1;106(1):274-86
pubmed: 15774621
Int J Mol Sci. 2020 Oct 16;21(20):
pubmed: 33081391
Blood Cancer J. 2016 Dec 9;6(12):e504
pubmed: 27935576
Science. 2014 Dec 12;346(6215):1373-7
pubmed: 25394790
Blood. 1993 Apr 15;81(8):2110-7
pubmed: 8471769
Blood. 2021 Nov 11;138(19):1855-1869
pubmed: 34125178
Nature. 2014 Jul 31;511(7511):616-20
pubmed: 25043025
Blood. 2004 Mar 1;103(5):1909-11
pubmed: 14604958
Blood Cancer Discov. 2020 Nov 24;2(1):19-31
pubmed: 34661151
Nat Commun. 2015 Jan 23;6:6094
pubmed: 25615415
EMBO J. 1990 Oct;9(10):3343-51
pubmed: 2209547
Haematologica. 2015 Jan;100(1):e10-3
pubmed: 25304610