A functional genetic link between αKG dehydrogenase activity and de novo nucleotide biosynthesis exists across cancers. (A) Gene codependency with OGDH across all cancers. The graph shows correlation (r; x-axis) and –log10(P value) (y-axis; genes with P > 10E-5 not shown) of gene dependency with OGDH dependency across all cancer types, based on composite depletion or enrichment of sgRNAs targeting individual genes across available CRISPR screens. A positive Pearson coefficient indicates gene codependency with OGDH. Selected genes of interest are labeled with blue indicating TCA enzymes; yellow, pyrimidine biosynthesis enzymes; and red, purine biosynthesis enzymes. (B) Schematic of the TCA cycle and its connectivity to purine and pyrimidine biosynthesis, highlighting significantly correlated OGDH codependencies as determined in the analysis depicted in panel A. (C) Gene codependency with OGDH in nonhematologic cancers. The analysis was conducted as in panel A, except that hematologic cancers were excluded. (D) Quantification of the correlation between OGDH and all genes encoding components of the de novo nucleotide biosynthesis pathway, nucleotide salvage pathway, or shared between these 2 pathways. P values are indicated (Kruskal-Wallis with Dunn multiple comparisons test). (E-F) Differential gene dependency in AML vs all non-AML (other) cancer types, based on difference of mean depletion or enrichment of sgRNAs targeting individual genes across available CRISPR screens. An y-axis value <0 indicates preferential dependency in AML, and an y-axis value >0 indicates preferential dependency in other cancer types. The highlighted genes are those encoding components of the de novo nucleotide synthesis pathway (E; green) and those encoding components of the nucleotide salvage pathway (F; gray). Each data point represents an individual gene. (G) Correlation of relative metabolite levels with OGDH dependency across all cancer cell types. A positive Pearson coefficient indicates relative enrichment of an individual metabolite in cells demonstrating OGDH dependency. Selected nucleotide precursors are labeled. CMP, cytidine 5′-monophosphate; GMP, guanosine monophosphate; ns, not significant.
