[en] Dysregulation of mRNA translation, including preferential translation of mRNA with complex 5'-UTRs such as the MYC oncogene, is recognized as an important mechanism in cancer. In this study, we show that both human and murine chronic lymphocytic leukemia (CLL) cells display a high translation rate, which can be inhibited by the synthetic flavagline FL3, a prohibitin (PHB)-binding drug. A multiomics analysis consisting of pulsed SILAC, RNA sequencing and polysome profiling performed in CLL patient samples and cell lines treated with FL3 revealed the decreased translation of the MYC oncogene and of proteins involved in cell cycle and metabolism. Furthermore, inhibition of translation was associated with a block of proliferation and a profound rewiring of MYC-driven 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 translation initiation complex and can be targeted by FL3. Knock-down of PHBs resembled FL3 treatment. Importantly, inhibition of translation was efficient in controlling 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 CLL patients. In conclusion, 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 CLL patients.
Disciplines :
Oncology
Author, co-author :
Largeot, Anne; Luxembourg Institute of Health, Luxembourg, Luxembourg
Klapp, Vanessa ; Faculty of Science, Technology and Medicine, University of Luxembourg, Luxembourg
Viry, Elodie; Luxembourg Institute of Health, Luxembourg, Luxembourg
Gonder, Susanne; Faculty of Science, Technology and Medicine, University of Luxembourg, Luxembourg
Fernandez Botana, Iria; Faculty of Science, Technology and Medicine, University of Luxembourg, Luxembourg
Blomme, Arnaud ; Université de Liège - ULiège > Département de pharmacie
Benzarti, Mohaned ; University of Luxembourg, Luxembourg
Pierson, Sandrine; Faculty of Science, Technology and Medicine, University of Luxembourg, Luxembourg
Duculty, Chloé ; Faculty of Science, Technology and Medicine, University of Luxembourg, Luxembourg
Marttila, Petra ; Science for Life Laboratory, Stockholm, Sweden
Wierz, Marina; Luxembourg Institute of Health, Luxembourg, Luxembourg
Gargiulo, Ernesto ; Luxembourg Institute of Health, Luxembourg, Luxembourg
Pagano, Giulia; University of Luxembourg, Department of Life Sciences and Medicine, Luxembourg
An, Ning ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling
El Hachem, Najla ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling
Perez Hermandez, Daniel ; Luxembourg Institute of Health, Strassen, Luxembourg
Chakraborty, Supriya; University of Luxembourg, Department of Life Sciences and Medicine, Luxembourg
Ysebaert, Loïc; Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
François, Jean-Hugues; University of Luxembourg, Department of Life Sciences and Medicine, Luxembourg
Cortez Clemente, Susan Denisse; Département d'hémato-oncologie, Centre Hospitalier de Luxembourg, Luxembourg
Berchem, Guy ; University of Luxembourg, Luxembourg
Efremov, Dimitar G; University of Luxembourg, Department of Life Sciences and Medicine, Luxembourg
Dittmar, Gunnar ; Département d'hémato-oncologie, Centre Hospitalier de Luxembourg, Luxembourg
Szpakowska, Martyna ; Département d'hémato-oncologie, Centre Hospitalier de Luxembourg, Luxembourg
Chevigné, Andy ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Département d'hémato-oncologie, Centre Hospitalier de Luxembourg, Luxembourg
Nazarov, Petr V ; Département d'hémato-oncologie, Centre Hospitalier de Luxembourg, Luxembourg
Helleday, Thomas; Département d'hémato-oncologie, Centre Hospitalier de Luxembourg, Luxembourg
Close, Pierre ; Université de Liège - ULiège > Département de pharmacie
Meiser, Johannes ; Département d'hémato-oncologie, Centre Hospitalier de Luxembourg, Luxembourg
Stamatopoulos, Basile; Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Alabama, Belgium
Désaubry, Laurent ; Université de Strasbourg, Illkirc, Illkirch, France
Paggetti, Jerome ; Luxembourg Institute of Health, Luxembourg, Luxembourg
Moussay, Etienne ; Luxembourg Institute of Health, Luxembourg, Luxembourg
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