Title

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

UMMS Affiliation

Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network

Date

6-1-2016

Document Type

Article

Disciplines

Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology

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 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.

Rights and Permissions

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

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

26876595