通过针对新鉴定的PHB-eIF4F复合物作为CLL治疗策略来抑制MYC翻译。
Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as therapeutic strategy in CLL.
发表日期：2023 Apr 21
作者：
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 Hermandez, Supriya Chakraborty, Loïc Ysebaert, Jean-Hugues François, Susan Denisse Cortez Clemente, Guy Berchem, Dimitar G Efremov, Gunnar Dittmar, Martyna Szpakowska, Andy Chevigne, Petr V Nazarov, Thomas Helleday, Pierre Close, Johannes Meiser, Basile Stamatopoulos, Laurent Désaubry, Jerome Paggetti, Etienne Moussay
来源：
BLOOD
摘要：
mRNA翻译的失调，包括复杂的5'-UTR序列的mRNA优先翻译，例如MYC癌基因，已被认为是癌症的重要机制。在本研究中，我们表明，人类和小鼠慢性淋巴细胞白血病（CLL）细胞都表现出高的翻译速率，这可以被合成的Flavagline FL3，一种抑制蛋白（PHB）结合药物所抑制。在CLL患者样本和受FL3处理的细胞系中进行的脉冲SILAC、RNA测序和多体蛋白质组分析显示，MYC癌基因和参与细胞周期和代谢的蛋白的翻译减少。此外，翻译抑制与增殖阻滞和MYC驱动的代谢深度重构相关。有趣的是，与其他模型相反，RAS-RAF-(PHBs)-MAPK通路在CLL细胞中既不受FL3影响也不参与翻译调控。在这里，我们展示了PHBs直接与翻译起始复合物相关，并且可以被FL3靶向。PHB的敲除类似于FL3的治疗。重要的是，翻译抑制在单独使用或与免疫治疗相结合的情况下，有效地控制了体内CLL的发展。最后，翻译起始相关基因和PHBs基因的高表达与CLL患者的不良预后和不利的临床参数相关。总之，我们证明了翻译抑制是控制CLL发展的有价值的策略，通过阻断包括MYC在内的多条致癌途径的翻译。我们还揭示了PHBs在翻译起始中的新的直接作用，从而为CLL患者创造了新的治疗机会。版权所有 © 2023美国血液学会。
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.Copyright © 2023 American Society of Hematology.