Abstract 1180: The TCA cycle transferase DLST is critical for MYC-mediated leukemogenesis

Abstract

Abstract The proto-oncogene MYC has been implicated in the pathogenesis of many human cancers, including hematological and solid malignancies1. In the majority of T-ALL cases, MYC is aberrantly expressed downstream of activated NOTCH1 mutations. 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 understood2. 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. Concordant with our zebrafish results, RNAi knockdown of DLST led to decreased cell viability and induction of apoptosis in human T-ALL cell lines. DLST is the E2 transferase of the -ketoglutarate dehydrogenase complex (KGDHC), which converts -ketoglutarate (-KG) to succinyl-CoA in the TCA cycle3. Polar metabolomics profiling revealed that the TCA cycle was disrupted by DLST knockdown in human T-ALL cells, as demonstrated by an accumulation of -KG and its precursor glutamine, as well as a loss 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. Taken together, our studies identify DLST as an important mediator of MYC-driven leukemogenesis and provide compelling evidence for the metabolic dependence of T-ALL cells on the TCA cycle. 1. Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene 1999 May 13; 18(19): 3004-3016. 2. Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L, et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Molecular and cellular biology 2006 Nov; 26(21): 8022-8031. 3. Sheu KF, Blass JP. The alpha-ketoglutarate dehydrogenase complex. Ann N Y Acad Sci 1999; 893: 61-78. Citation Format: Nicole Anderson, Dun Li, H.L. Peng, Marc Mansour, Fabrice Laroche, Evisa Gjini, Daniel Helman, Itrat Harrold, Le Meng, Takaomi Sanda, Adam Amsterdam, Donna Neuberg, Travis Denton, Anurag Singh, A Thomas Look, Hui Feng. The TCA cycle transferase DLST is critical for MYC-mediated leukemogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1180.