Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as a therapeutic strategy in CLL

Anne Largeot, Vanessa Klapp, Elodie Viry, Susanne Gonder, Iria Fernandez Botana, Arnaud Blomme, Mohaned Benzarti*, Sandrine Pierson, Chloé Duculty, Petra Marttila, Marina Wierz, Ernesto Gargiulo, Giulia Pagano, Ning An, Najla El Hachem, Daniel Perez Hernandez, Supriya Chakraborty, Loïc Ysebaert, Jean Hugues François, Susan Cortez ClementeGuy Berchem, Dimitar G. Efremov, Gunnar Dittmar, Martyna Szpakowska, Andy Chevigné, Petr V. Nazarov, Thomas Helleday, Pierre Close, Johannes Meiser, Basile Stamatopoulos, Laurent Désaubry, Jérôme Paggetti* (Main author), Etienne Moussay (Main author)

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

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 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 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.

Original languageEnglish
Pages (from-to)3166-3183
Number of pages18
JournalBlood
Volume141
Issue number26
Early online date21 Apr 2023
DOIs
Publication statusPublished - 29 Jun 2023

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