Harnessing the MYB-dependent TAL1 5’super-enhancer for targeted therapy in T-ALL
oleh: Charlotte Smith, Aurore Touzart, Mathieu Simonin, Christine Tran-Quang, Guillaume Hypolite, Mehdi Latiri, Guillaume P. Andrieu, Estelle Balducci, Marie-Émilie Dourthe, Ashish Goyal, Françoise Huguet, Arnaud Petit, Norbert Ifrah, André Baruchel, Hervé Dombret, Elizabeth Macintyre, Christoph Plass, Jacques Ghysdael, Nicolas Boissel, Vahid Asnafi
| Format: | Article |
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| Diterbitkan: | BMC 2023-01-01 |
Deskripsi
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.