The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis
Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
Despite the pivotal role of MYC in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and many other cancers, the mechanisms underlying MYC-mediated tumorigenesis remain inadequately understood. Here we utilized a well-characterized zebrafish model of Myc-induced T-ALL for genetic studies to identify novel genes contributing to disease onset. We found that heterozygous inactivation of a tricarboxylic acid (TCA) cycle enzyme, dihydrolipoamide S-succinyltransferase (Dlst), significantly delayed tumor onset in zebrafish without detectable effects on fish development. DLST is the E2 transferase of the alpha-ketoglutarate (alpha-KG) dehydrogenase complex (KGDHC), which converts alpha-KG to succinyl-CoA in the TCA cycle. RNAi knockdown of DLST led to decreased cell viability and induction of apoptosis in human T-ALL cell lines. Polar metabolomics profiling revealed that the TCA cycle was disrupted by DLST knockdown in human T-ALL cells, as demonstrated by an accumulation of alpha-KG and a decrease of succinyl-CoA. Addition of succinate, the downstream TCA cycle intermediate, to human T-ALL cells was sufficient to rescue defects in cell viability caused by DLST inactivation. Together, our studies uncovered an important role for DLST in MYC-mediated leukemogenesis and demonstrated the metabolic dependence of T-lymphoblasts on the TCA cycle, thus providing implications for targeted therapy.
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Citation: Leukemia. 2016 Jun;30(6):1365-74. doi: 10.1038/leu.2016.26. Epub 2016 Feb 15. Link to article on publisher's site
Anderson, N. M.; Kelliher, Michelle A.; and Feng, H., "The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis" (2016). UMass Metabolic Network Publications. 41.