期刊
LEUKEMIA
卷 30, 期 6, 页码 1365-1374出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.26
关键词
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资金
- National Institute of Health [K99CA134743/R00CA134743, 1R01 CA176746]
- Karin Grunebaum faculty fellowship from the Karin Grunebaum Cancer Foundation
- Ralph Edwards Career Development Professorship from Boston University
- St Baldrick Scholar Award from the St Baldrick's Foundation
- American Cancer Society [IRG -72-001-36-IRG]
- Leukemia Research Foundation
- NSFC [81200368]
- [NHLB1 T32 HL007501]
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.
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