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Article Dans Une Revue Molecular Cancer Année : 2023

Harnessing the MYB-dependent TAL1 5’super-enhancer for targeted therapy in T-ALL

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.
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hal-04087807 , version 1 (03-05-2023)

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Charlotte Smith, Aurore Touzart, Mathieu Simonin, Christine Tran-Quang, Guillaume Hypolite, et al.. Harnessing the MYB-dependent TAL1 5’super-enhancer for targeted therapy in T-ALL. Molecular Cancer, 2023, 22 (1), pp.12. ⟨10.1186/s12943-022-01701-x⟩. ⟨hal-04087807⟩

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