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.

• Authors: N M Anderson, D Li, H L Peng, F J F Laroche, M R Mansour, E Gjini, M Aioub, D J Helman, J E Roderick, T Cheng, I Harrold, Y Samaha, L Meng, A Amsterdam, D S Neuberg, T T Denton, T Sanda, M A Kelliher, A Singh, A T Look, H Feng
• Journal: Leukemia (Leukemia) Vol. 30 Issue 6 Pg. 1365-74 (06 2016) ISSN: 1476-5551 [Electronic] England
• PMID: 26876595 (Publication Type: Journal Article)

Chemical References

• Acyl Coenzyme A
• Ketoglutaric Acids
• Proto-Oncogene Proteins c-myc
• succinyl-coenzyme A
• Acyltransferases
• dihydrolipoamide succinyltransferase

Topics

• Acyl Coenzyme A (metabolism)
• Acyltransferases (physiology)
• Animals
• Apoptosis
• Carcinogenesis
• Cell Line, Tumor
• Cell Survival
• Citric Acid Cycle
• Humans
• Ketoglutaric Acids (metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (etiology, metabolism, pathology)
• Proto-Oncogene Proteins c-myc (metabolism)
• Zebrafish