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

Molecular Cancer

Correspondence

Françoise Huguet¹  André Baruchel²  Ashish Goyal³  Christoph Plass⁴  Jacques Ghysdael⁵  Christine Tran-Quang⁵  Arnaud Petit⁶  Norbert Ifrah⁷  Elizabeth Macintyre⁸  Mathieu Simonin⁸  Estelle Balducci⁸  Guillaume P. Andrieu⁸  Vahid Asnafi⁸  Charlotte Smith⁸  Aurore Touzart⁸  Guillaume Hypolite⁸  Mehdi Latiri⁸  Marie-Émilie Dourthe⁹  Nicolas Boissel^1,10  Hervé Dombret^1,10 

[1] Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Laboratoire d’Hématologie, Toulouse, France;Department of Pediatric Hematology and Immunology, Assistance Publique-Hôpitaux de Paris (AP-HP), Robert Debré Hospital, Université de Paris Cité, Paris, France;Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;German Cancer Research Consortium (DKTK), 69120, Heidelberg, Germany;Institut Curie, Orsay, France;CNRS UMR3348, Institut Curie, Orsay, France;INSERM U1278, Centre Universitaire, Orsay, France;PSL Research University, Paris, France;University Paris-Saclay, 91400, Orsay, France;Service d’Hématologie Et d’Oncologie Pédiatrique, AP-HP, Hôpital Armand Trousseau, Sorbonne Université, Paris, France;UFR Santé, Université Angers, PRES LUNAM, Centre Hospitalier-Universitaire (CHU) d’Angers, Service Des Maladies du Sang Et INSERM U892, 49933, Angers, France;Université de Paris Cité, Institut Necker Enfants-Malades INEM, Institut National de La Santé Et de La Recherche Médicale (Inserm), U1151, Paris, France;Laboratory of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades 75743, Paris, France;Université de Paris Cité, Institut Necker Enfants-Malades INEM, Institut National de La Santé Et de La Recherche Médicale (Inserm), U1151, Paris, France;Laboratory of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades 75743, Paris, France;Department of Pediatric Hematology and Immunology, Assistance Publique-Hôpitaux de Paris (AP-HP), Robert Debré Hospital, Université de Paris Cité, Paris, France;Université de Paris Cité, Institut Universitaire d’Hématologie, EA-3518, Assistance Publique-Hôpitaux de Paris, University Hospital Saint-Louis, Paris, France;

关键词: Super-enhancer;    Oncogene;    Targeted therapy;    Cancer;   

DOI  :  10.1186/s12943-022-01701-x

 received in 2022-11-21, accepted in 2022-12-16,  发布年份 2022

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

41116_2022_35_Article_IEq561.gif

Fig. 1

Fig. 2

41116_2022_35_Article_IEq512.gif