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

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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

Edité par CCSD ; BioMed Central -

International audience. 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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