15 research outputs found
Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction
The transcription factor Nrf2 regulates
the expression of a large
network of cytoprotective and metabolic enzymes and proteins. Compounds
that directly and reversibly inhibit the interaction between Nrf2
and its main negative regulator Keap1 are potential pharmacological
agents for a range of disease types including neurodegenerative conditions
and cancer. We describe the development of a series of 1,4-diphenyl-1,2,3-triazole
compounds that inhibit the Nrf2–Keap1 protein–protein
interaction (PPI) in vitro and in live
cells and up-regulate the expression of Nrf2-dependent gene products
ETO2-GLIS2 hijacks transcriptional complexes to drive cellular identity and self-renewal in pediatric acute megakaryoblastic leukemia
Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.Cécile Thirant, Cathy Ignacimouttou, Cécile K. Lopez, M’Boyba Diop, Lou Le Mouël, Clarisse Thiollier, Aurélie Siret, Phillipe Dessen, Zakia Aid, Julie Rivière, Philippe Rameau, Céline Lefebvre, Mehdi Khaled, Guy Leverger, Paola Ballerini, Arnaud Petit, Hana Raslova, Catherine L. Carmichael, Benjamin T. Kile, Eric Soler, John D. Crispino, Christian Wichmann, Francoise Pflumio, Jürg Schwaller, William Vainchenker, Camille Lobry, Nathalie Droin, Olivier A. Bernard, Sébastien Malinge, and Thomas Merche