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