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- Title
Harnessing the MYB-dependent TAL1 5'super-enhancer for targeted therapy in T-ALL.
- Authors
Smith, Charlotte; Touzart, Aurore; Simonin, Mathieu; Tran-Quang, Christine; Hypolite, Guillaume; Latiri, Mehdi; Andrieu, Guillaume P.; Balducci, Estelle; Dourthe, Marie-Émilie; Goyal, Ashish; Huguet, Françoise; Petit, Arnaud; Ifrah, Norbert; Baruchel, André; Dombret, Hervé; Macintyre, Elizabeth; Plass, Christoph; Ghysdael, Jacques; Boissel, Nicolas; Asnafi, Vahid
- 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.
- Subjects
CELL death; PROTO-oncogenes; PROTEOLYSIS; LYMPHOBLASTIC leukemia; ONCOGENES; ACUTE leukemia
- Publication
Molecular Cancer, 2023, Vol 22, Issue 1, p1
- ISSN
1476-4598
- Publication type
Article
- DOI
10.1186/s12943-022-01701-x