According to the results of a study published in Nature, deregulation of valine transfer RNA (tRNA) appears to be a critical adaptation in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). The finding provides a molecular basis for the use of dietary approaches targeting tRNA biogenesis in blood cancers.
“Although deregulation of [tRNA] biogenesis promotes the translation of pro-tumorigenic mRNAs in cancers, the mechanisms and consequences of tRNA deregulation in tumorigenesis are poorly understood,” Palaniraja Thandapani, PhD, of NYU Langone Medical Center, New York, and colleagues wrote in their report.
To determine whether tRNA biogenesis is deregulated in blood cancers, the researchers focused on T-ALL—which currently has no US Food and Drug Administration-approved targeted therapies. They used CRISPR–Cas9 gene editing to selectively target genes that have been implicated previously in tRNA biogenesis. This loss-of-function negative-selection screen revealed that the gene encoding valine aminoacyl tRNA synthetase, which loads valine tRNAs with valine, was among the top-depleted genes in T-ALL cell lines.
The team went on to demonstrate that transcription of the valine aminoacyl tRNA synthetase gene is upregulated by NOTCH1, a known oncogene responsible for the majority of T-ALL cases.
Because valine is an essential amino acid that must be acquired through diet, the researchers hypothesized that dietary restriction of valine might reduce the survival of T-ALL cells. To test this hypothesis, they used a preclinical NOTCH1-driven T-ALL mouse model. Limiting valine via dietary restriction resulted in increased apoptosis of the leukemic blasts, decreased leukemic burden, and reduced splenomegaly in vivo as well as increased survival of the mice.
To evaluate the effects of dietary valine restriction in T-ALL, the researchers assessed changes in active translation in splenic blasts from the mice. They found that valine restriction reduced translation rates of mRNAs that encode subunits of mitochondrial complex I. Through further examination of cultured T-ALL cell lines, they showed that valine restriction reduced mitochondrial complex I formation, which was associated with defective mitochondrial function.
Using electron microscopy-based morphometric analysis, they demonstrated that reduced complex I formation and mitochondrial activity was associated with increased width of the crista lumen and disorganization of the inner mitochondrial membrane.
Lastly, the team conducted a genome-wide loss-of-function CRISPR-Cas9 screen of T-ALL cells under varying valine conditions and identified several genes, including SLC7A5 and BCL2, whose genetic ablation or pharmacological inhibition synergized with valine restriction to reduce T-ALL growth. These gene represent potential targets for combination therapies with controlled dietary valine restriction.
“In summary, we have identified a mechanism by which altered valine tRNA biogenesis can enhance mitochondrial bioenergetics by regulating the synthesis of ETC complex I proteins in human acute leukemia,” concluded the authors. “Notably, dietary manipulation of valine is used clinically in the management of metabolic diseases, such as propionic and methylmalonic acidemias, and may effectively synergize with targeted therapies in the treatment of human T-ALL.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Thandapani P, Kloetgen A, Witkowski MT, et al. Valine tRNA levels and availability regulate complex I assembly in leukaemia. Nature. 2022;601(7893):428-433. doi:10.1038/s41586-021-04244-1