The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences; The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Commun. 2021 Nov 11;12(1):6506. doi: 10.1038/s41467-021-26867-8.
CRISPR knockout fitness screens in cancer cell lines reveal many genes whose loss of function causes cell death or loss of fitness or, more rarely, the opposite phenotype of faster proliferation. Here we demonstrate a systematic approach to identify these proliferation suppressors, which are highly enriched for tumor suppressor genes, and define a network of 145 such genes in 22 modules. One module contains several elements of the glycerolipid biosynthesis pathway and operates exclusively in a subset of acute myeloid leukemia cell lines. The proliferation suppressor activity of genes involved in the synthesis of saturated fatty acids, coupled with a more severe loss of fitness phenotype for genes in the desaturation pathway, suggests that these cells operate at the limit of their carrying capacity for saturated fatty acids, which we confirm biochemically. Overexpression of this module is associated with a survival advantage in juvenile leukemias, suggesting a clinically relevant subtype.
CRISPR 基因敲除细胞活力筛选在癌细胞系中揭示了许多基因，其功能丧失会导致细胞死亡或活力丧失，或者更罕见的是相反的增殖表型。在这里，我们展示了一种系统的方法来识别这些增殖抑制剂，它们高度富集了肿瘤抑制基因，并在 22 个模块中定义了一个包含 145 个这样基因的网络。一个模块包含甘油磷脂生物合成途径的几个元素，并且仅在急性髓系白血病细胞系的一个亚集中起作用。参与饱和脂肪酸合成的基因的增殖抑制活性，加上去饱和途径中基因的更严重的丧失活力表型，表明这些细胞在饱和脂肪酸的承载能力极限处运作，我们通过生化方法证实了这一点。该模块的过表达与青少年白血病中的生存优势相关，提示存在一种具有临床相关性的亚型。
