TY - JOUR
T1 - Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as therapeutic strategy in CLL
AU - Largeot, Anne
AU - Klapp, Vanessa
AU - Viry, Elodie
AU - Gonder, Susanne
AU - Fernandez Botana, Iria
AU - Blomme, Arnaud
AU - Benzarti, Mohaned
AU - Pierson, Sandrine
AU - Duculty, Chloé
AU - Marttila, Petra
AU - Wierz, Marina
AU - Gargiulo, Ernesto
AU - Pagano, Giulia
AU - An, Ning
AU - El Hachem, Najla
AU - Perez Hermandez, Daniel
AU - Chakraborty, Supriya
AU - Ysebaert, Loïc
AU - François, Jean-Hugues
AU - Cortez Clemente, Susan Denisse
AU - Berchem, Guy
AU - Efremov, Dimitar G
AU - Dittmar, Gunnar
AU - Szpakowska, Martyna
AU - Chevigne, Andy
AU - Nazarov, Petr V
AU - Helleday, Thomas
AU - Close, Pierre
AU - Meiser, Johannes
AU - Stamatopoulos, Basile
AU - Désaubry, Laurent
AU - Paggetti, Jerome
AU - Moussay, Etienne
N1 - Funding:This work was supported by grants from the Luxembourg National Research Fund (FNR) and Fondation Cancer to VK, EG, CD, EM and JP (PRIDE19/14254520/i2TRON, PRIDE15/10675146/CANBIO, PRIDE21/16763386, C20/BM/14582635, and C20/BM/14592342), to AC/MS (INTER/FNRS/20/15084569) and to JM (ATTRACT grant A18/BM/11809970), from FNRS-Télévie to AL (7.4502.17, 7.4503.19), EV (7.4509.20), and SG (7.4502.19 ,7.6604.21), GP (7.4501.18, 7.6518.20), IFB (7.4529.19, 7.6603.21), MW (7.4508.16, 7.6504.18), AC/MS (7.8508.22, 7.8504.20 and 7.4593.19), from the Plooschter Projet to JP and EM, from the Belgian Foundation for Cancer Research to PC (N°2020-068), and from the Swedish Children’s Cancer Foundation (PR2021-003), the Swedish Research Council (2015-00162), and Swedish Cancer Society (21 1490) to TH.
Copyright © 2023 American Society of Hematology.
PY - 2023/4/21
Y1 - 2023/4/21
N2 - 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.
AB - 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.
UR - https://pubmed.ncbi.nlm.nih.gov/37084385/
U2 - 10.1182/blood.2022017839
DO - 10.1182/blood.2022017839
M3 - Article
C2 - 37084385
SN - 0006-4971
JO - Blood
JF - Blood
ER -