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Harnessing the MYB-dependent TAL1 5’super-enhancer for targeted therapy in T-ALL
- Source :
- Molecular Cancer, Vol 22, Iss 1, Pp 1-7 (2023)
- Publication Year :
- 2023
- Publisher :
- BMC, 2023.
-
Abstract
- Abstract 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.
Details
- Language :
- English
- ISSN :
- 14764598
- Volume :
- 22
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Molecular Cancer
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.4734bedc577342f6ab4cb273d503e554
- Document Type :
- article
- Full Text :
- https://doi.org/10.1186/s12943-022-01701-x