Year: 2025
Type: article
Abstract: in mitochondrial protein synthesis, the authors investigated if changes in mitochondrial respiration contribute to the synthetic lethality of TRMT5 loss in the presence of AraC.Chemotherapypersistence is defined as a temporary condition in which a population of AML cells can survive during chemotherapy treatment without overt genetic resistance.Here, the AraC-persistent cell lines exhibited the lowest oxygen consumption rates and the lowest electron transport chain gene expression compared to AraCsensitive AML cell lines.Importantly, due to their capacity to increase mitochondrial protein synthesis, AraC-persistent cells were able to rapidly increased oxygen consumption upon exposure to chemotherapy, whereas the AraC-sensitive cell lines could not.This rapid increase in oxygen consumption in AraC-persistent cells was prevented by loss of TRMT5, which also restored chemotherapy sensitivity.The authors were able to identify patients with chemotherapy resistance through the low expression of mitochondrial electron transport chain genes, a finding that was confirmed in multiple independent data sets.This finding appeared to be independent of adverse genetic features, such as p53 loss of function, although a comprehensive multivariate analysis was not possible due to patient numbers.The authors also used an elegant inducible system in which TRMT5 could be degraded (the dTAG system), to demonstrate specificity and proof of principle that degrading TRMT5 synergized with the effects of chemotherapy and venetoclax, indicating that this approach may be relevant to low-intensity approaches in addition to restoring response to intensive chemotherapy.This work extends our understanding of the complex and tightly regulated processes that govern RNA biology and conceptually provides proof of principle that modulating RNA modifications can be leveraged to develop new therapies for patients with blood cancers.
Source: Blood
Authors: Senthil Sukumar, Spero R. Cataland
Institutions: Baylor College of Medicine, The Ohio State University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416186530