ИСТИНА

Background: Proteins MCTS1 and DENR are known to be involved in protein biosynthesis regulated by reinitiation translation and ribosome recycling. It was shown that increased expression of these proteins is often detected in various malignant diseases, including lymphoma however, their role in blood cancers remains unknown. Aims: Here we aimed to study the role of MCTS1 and DENR proteins in the regulation of signaling pathways, associated with malignant transformation in leukemia/lymphoma cells. Methods: We used RNA-interfence approach to down-regulate the MCTS1 or DENR genes in T-leukemia/lymphoma cells and performed RNAseq analysis and analysis of signaling pathways using gene annotation platforms. The cell lines with CRISPR/CAS9 induced knockout of MCTS1 gene were obtained and shRNA-induced suppression of DENR in these cells was performed. Connectivity Map (CMAP) analysis was performed and the sensitivity to anti-cancer drugs was measured. Results: We found that among all differentially varying signaling pathways, more than a half of signaling pathways that change in response to DENR suppression were found to be common with those that change in response to suppression of MCTS1. Moreover, they make up more than a half of all pathways whose activity changes in response to the suppression of MCTS1. It was shown that suppression of DENR leads to a significant activation of signaling cascades associated with decreased sensitivity to anti-cancer drugs. It is essential that suppression of MCTS1 expression led to the suppression of the same pathways demonstrating a strong interplay between these factors and their targets. We demonstrated that the suppression of DENR, leads to decreased sensitivity of leukemia/lymphoma cells to anti-cancer drugs. Summary/Conclusion: Our data suggests that protein DENR and its associated protein MCTS1 may be involved in mechanisms defining better response of leukemia/lymphoma cells to anti-cancer drugs. This work was supported by Russian Foundation for Basic Research (grant № 20-04-00923)