The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis

Abstract

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 (α-KG) dehydrogenase complex (KGDHC), which converts 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.

Simultaneous B and T cell acute lymphoblastic leukemias in zebrafish driven by transgenic MYC: implications for oncogenesis and lymphopoiesis

“…3A), with both ALL types showing comparable levels of rag2, hMYC , and shmt2 , a known direct MYC target (Fig. S5A) (21), reinforcing that hMYC levels and activity are similar in this dual pre-B/T-ALL model. To further examine conservation of gene expression between both types of D. rerio and human ALL, we also tested whether human homologues of the differentially-expressed hMYC pre-B-vs. T-ALL genes could reliably classify ALL from the MILE1 study (Fig.…”

The emerging role and targetability of the TCA cycle in cancer metabolism

“…OGDH is regulated by Ca 2+ , adenine nucleotides, and NADH, and the tumor-specific isoform lacks three regions of the protein and exhibits reduced sensitivity to Ca 2+ . Additionally, Anderson et al found that the E2 component of KGDHC, DLST, is upregulated in T-cell acute lymphoblastic leukemia (T-ALL) (Anderson et al, 2016 ).…”

Nicotinamide N‐methyltransferase expression in SH‐SY5Y human neuroblastoma cells decreases oxidative stress

“…In addition, the uncoupling of glycolysis from the Krebs cycle reduces the ATP yield per glucose molecule from 38 to 2. The tumour cell compensates for this somewhat by increasing glycolytic flux, driven by an increase in the expression of the high‐affinity glucose transporters GluT1 and GluT3 . However, recent evidence suggests that some cancers, for example, gliomas and myelomas, use alternative fuel sources such as glutamine to drive the Krebs cycle and subsequently generate ATP, to offset this loss in ATP production .…”