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Valine tRNA levels and availability influence blood malignancies: a molecular basis for the use of dietary approaches in these tumors
Recent findings have highlighted that altered tRNA biogenesis and resultant changes in codon usage could have a relevant role in the translation of cancer genomes, but the mechanisms and consequences of tRNA deregulation in tumorigenesis are poorly understood. A new study, recently published on Nature, sheds a new light on these mechanisms by the analysis of valine tRNA biogenesis in T cell acute lymphoblastic leukaemia.
Authors, by using a CRISPR–Cas9 screen to focus on genes that have been implicated in tRNA biogenesis, identified a mechanism by which altered valine tRNA biogenesis enhances mitochondrial bioenergetics: expression of valine aminoacyl tRNA synthetase is transcriptionally upregulated by a key oncogene, underlining a role for oncogenic transcriptional programs in coordinating tRNA supply and demand. Data shows that limiting valine bioavailability through restriction of dietary valine intake disrupted this balance in mice, resulting in decreased leukaemic burden and increased survival in vivo. Authors, after a thorough analysis of the mechanisms that led to tRNA biogenesis disruption, found that valine tRNA levels and availability regulate mitochondrial complex I assembly. By identifying tRNA deregulation as a critical adaptation in the pathogenesis of T cell acute lymphoblastic leukaemia, these data provide a molecular basis for the use of dietary approaches to target tRNA biogenesis in blood malignancies.