학술논문
Harnessing the MYB-dependent TAL1 5’super-enhancer for targeted therapy in T-ALL
Document Type
article
Author
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
Source
Molecular Cancer, Vol 22, Iss 1, Pp 1-7 (2023)
Subject
Language
English
ISSN
1476-4598
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.