Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as a therapeutic strategy in CLL
2023
Largeot, Anne | Klapp, Vanessa | Viry, Elodie | Gonder, Susanne | Fernandez Botana, Iria | Blomme, Arnaud | Benzarti, Mohaned | Pierson, Sandrine | Duculty, Chloé | Marttila, Petra | Wierz, Marina | Gargiulo, Ernesto | Pagano, Giulia | An, Ning | Hachem, Najla, El | Perez Hernandez, Daniel | Chakraborty, Supriya | Ysebaert, Loïc | François, Jean-Hugues | Clemente, Susan, Cortez | Berchem, Guy | Efremov, Dimitar, G | Dittmar, Gunnar | Szpakowska, Martyna | Chevigné, Andy | Nazarov, Petr, V | Helleday, Thomas | Close, Pierre | Meiser, Johannes | Stamatopoulos, Basile | Désaubry, Laurent | Paggetti, Jerome | Moussay, Etienne | Luxembourg Institute of Health (LIH) | Université du Luxembourg = University of Luxembourg = Universität Luxemburg (uni.lu) | GIGA Institute [Université de Liège] (GIGA [Liège]) ; Université de Liège = University of Liège = Universiteit van Luik = Universität Lüttich (ULiège) | Karolinska Institutet [Stockholm] | International Centre for Genetic Engineering and Biotechnology [Trieste, Italy] (ICGEB) | Centre de Recherches en Cancérologie de Toulouse (CRCT) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Service Hématologie - IUCT-Oncopole [CHU Toulouse] ; Pôle Biologie [CHU Toulouse] ; Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse] ; Centre Hospitalier Universitaire de Toulouse (CHU Toulouse) | Centre Hospitalier de Luxembourg [Luxembourg] (CHL) | University of Sheffield [Sheffield] | Cancer Research Centre, Weston Park Hospital | WELBIO Department, WEL Research Institute, Avenue Pasteur, 6, 1300, Wavre | Institut Jules Bordet [Bruxelles] ; Faculté de Médecine [Bruxelles] (ULB) ; Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB) | Université libre de Bruxelles (ULB) | Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN) ; Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Fédération de Médecine Translationnelle de Strasbourg (FMTS) ; Université de Strasbourg (UNISTRA)
International audience
Mostrar más [+] Menos [-]Inglés. <div><p>Inhibition of translation initiation prevents CLL growth in vitro and in vivo, through targeting the MYC oncogene.</p><p>• PHBs directly interact with the translation initiation machinery, filling a gap in the understanding of the crucial roles of these proteins.</p><p>Dysregulation of messenger RNA (mRNA) translation, including preferential translation of mRNA with complex 5′ untranslated regions such as the MYC oncogene, is recognized as an important mechanism in cancer. Here, we show that both human and murine chronic lymphocytic leukemia (CLL) cells display a high translation rate, which is inhibited by the synthetic flavagline FL3, a prohibitin (PHB)-binding drug. A multiomics analysis performed in samples from patients with CLL and cell lines treated with FL3 revealed the decreased translation of the MYC oncogene and of proteins involved in cell cycle and metabolism. Furthermore, inhibiting translation induced a proliferation arrest and a rewiring of MYCdriven metabolism. Interestingly, contrary to other models, the RAS-RAF-(PHBs)-MAPK pathway is neither impaired by FL3 nor implicated in translation regulation in CLL cells. Here, we rather show that PHBs are directly associated with the eukaryotic initiation factor (eIF)4F translation complex and are targeted by FL3. Knockdown of PHBs resembled FL3 treatment. Importantly, inhibition of translation controlled CLL development in vivo, either alone or combined with immunotherapy. Finally, high expression of translation initiation-related genes and PHBs genes correlated with poor survival and unfavorable clinical parameters in patients with CLL. Overall, we demonstrated that translation inhibition is a valuable strategy to control CLL development by blocking the translation of several oncogenic pathways including MYC. We also unraveled a new and direct role of PHBs in translation initiation, thus creating new therapeutic opportunities for patients with CLL. Treg CD4 + T CD8 + T CLL B Eμ-TCL1 splenocytes</p></div>
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