论文
论文标题：Valine tRNA levels and availability regulate complex I assembly in leukaemia
作者：Thandapani, Palaniraja, Kloetgen, Andreas, Witkowski, Matthew T., Glytsou, Christina, Lee, Anna K., Wang, Eric, Wang, Jingjing, LeBoeuf, Sarah E., Avrampou, Kleopatra, Papagiannakopoulos, Thales, Tsirigos, Aristotelis, Aifantis, Iannis
期刊：Nature
发表时间：2021/12/22
数字识别码：10.1038/s41586-021-04244-1
摘要：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.
所属学科：
医学
美国纽约大学朗格尼健康中心（NYU Langone Health）的一项新研究表明，肉、鱼和豆类富含的氨基酸缬氨酸（valine）可促进 T 细胞急性淋巴细胞白血病中的癌症生长，该疾病高发于儿童。体外实验表明，与正常 T 细胞相比，消耗缬氨酸的基因在癌性 T 细胞中更为活跃；阻断这些与缬氨酸相关的基因不仅会导致白血病患者外周血 T 细胞中缬氨酸的减少，还将癌性细胞活性降低至 2% 。进一步的实验表明，给白血病小鼠喂食低缬氨酸饮食三周将循环血癌细胞减少至原来的一半以下，阻止了肿瘤生长。反之，在饮食中重新引入缬氨酸会促进癌症发展。
