Anderson, N.M., Li, D., Peng, H.L., Laroche, F.J., Mansour, M.R., Gjini, E., Aioub, M., Helman, D.J., Roderick, J.E., Cheng, T., Harrold, I., Samaha, Y., Meng, L., Amsterdam, A., Neuberg, D.S., Denton, T.T., Sanda, T., Kelliher, M.A., Singh, A., Look, A.T., Feng, H. (2016) The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia. 30(6):1365-74.
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 α-ketoglutarate dehydrogenase complex (KGDHC), which converts α-ketoglutarate (α-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 α-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.