TY  - JOUR
AU  - Smith, Charlotte
AU  - Touzart, Aurore
AU  - Simonin, Mathieu
AU  - Tran-Quang, Christine
AU  - Hypolite, Guillaume
AU  - Latiri, Mehdi
AU  - Andrieu, Guillaume P
AU  - Balducci, Estelle
AU  - Dourthe, Marie-Émilie
AU  - Goyal, Ashish
AU  - Huguet, Françoise
AU  - Petit, Arnaud
AU  - Ifrah, Norbert
AU  - Baruchel, André
AU  - Dombret, Hervé
AU  - Macintyre, Elizabeth
AU  - Plass, Christoph
AU  - Ghysdael, Jacques
AU  - Boissel, Nicolas
AU  - Asnafi, Vahid
TI  - Harnessing the MYB-dependent TAL1 5'super-enhancer for targeted therapy in T-ALL.
JO  - Molecular cancer
VL  - 22
IS  - 1
SN  - 1476-4598
CY  - London
PB  - Biomed Central
M1  - DKFZ-2023-00111
SP  - 12
PY  - 2023
AB  - 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.
KW  - Cancer (Other)
KW  - Oncogene (Other)
KW  - Super-enhancer (Other)
KW  - Targeted therapy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36650499
DO  - DOI:10.1186/s12943-022-01701-x
UR  - https://inrepo02.dkfz.de/record/186783
ER  -