Valine tRNA levels and availability regulate complex I assembly in leukaemia

Palaniraja Thandapani (), Andreas Kloetgen, Matthew T. Witkowski, Christina Glytsou, Anna K. Lee, Eric Wang, Jingjing Wang, Sarah E. LeBoeuf, Kleopatra Avrampou, Thales Papagiannakopoulos, Aristotelis Tsirigos and Iannis Aifantis ()
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Palaniraja Thandapani: NYU School of Medicine
Andreas Kloetgen: NYU School of Medicine
Matthew T. Witkowski: NYU School of Medicine
Christina Glytsou: NYU School of Medicine
Anna K. Lee: NYU School of Medicine
Eric Wang: NYU School of Medicine
Jingjing Wang: NYU School of Medicine
Sarah E. LeBoeuf: NYU School of Medicine
Kleopatra Avrampou: NYU School of Medicine
Thales Papagiannakopoulos: NYU School of Medicine
Aristotelis Tsirigos: NYU School of Medicine
Iannis Aifantis: NYU School of Medicine

Nature, 2022, vol. 601, issue 7893, 428-433

Abstract: Abstract Although deregulation of transfer RNA (tRNA) biogenesis promotes the translation of pro-tumorigenic mRNAs in cancers1,2, the mechanisms and consequences of tRNA deregulation in tumorigenesis are poorly understood. Here we use a CRISPR–Cas9 screen to focus on genes that have been implicated in tRNA biogenesis, and identify a mechanism by which altered valine tRNA biogenesis enhances mitochondrial bioenergetics in T cell acute lymphoblastic leukaemia (T-ALL). Expression of valine aminoacyl tRNA synthetase is transcriptionally upregulated by NOTCH1, a key oncogene in T-ALL, underlining a role for oncogenic transcriptional programs in coordinating tRNA supply and demand. Limiting valine bioavailability through restriction of dietary valine intake disrupted this balance in mice, resulting in decreased leukaemic burden and increased survival in vivo. Mechanistically, valine restriction reduced translation rates of mRNAs that encode subunits of mitochondrial complex I, leading to defective assembly of complex I and impaired oxidative phosphorylation. Finally, a genome-wide CRISPR–Cas9 loss-of-function screen in differential valine conditions identified several genes, including SLC7A5 and BCL2, whose genetic ablation or pharmacological inhibition synergized with valine restriction to reduce T-ALL growth. Our findings identify tRNA deregulation as a critical adaptation in the pathogenesis of T-ALL and provide a molecular basis for the use of dietary approaches to target tRNA biogenesis in blood malignancies.

Date: 2022
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DOI: 10.1038/s41586-021-04244-1

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