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The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis.
N M Anderson1, D Li1, H L Peng2,3
1Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
Leukemia
|February 16, 2016
Summary
Dihydrolipoamide S-succinyltransferase (DLST), a key enzyme in the tricarboxylic acid cycle, is crucial for MYC-driven T-cell acute lymphoblastic leukemia (T-ALL) development. Its inactivation delays tumor onset and impacts T-ALL cell metabolism.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer genetics
Background:
- MYC is a critical oncogene in T-cell acute lymphoblastic leukemia (T-ALL) and other cancers.
- Mechanisms of MYC-driven tumorigenesis are not fully understood.
Purpose of the Study:
- Identify novel genes involved in MYC-induced T-ALL pathogenesis.
- Investigate the role of the tricarboxylic acid (TCA) cycle enzyme dihydrolipoamide S-succinyltransferase (DLST) in MYC-mediated leukemogenesis.
Main Methods:
- Utilized a zebrafish model of Myc-induced T-ALL for genetic studies.
- Performed RNAi knockdown of DLST in human T-ALL cell lines.
- Conducted polar metabolomics profiling to analyze TCA cycle disruption.
- Assessed cell viability and apoptosis induction.
Main Results:
- Heterozygous inactivation of DLST significantly delayed tumor onset in zebrafish T-ALL models.
- DLST knockdown decreased cell viability and induced apoptosis in human T-ALL cells.
- DLST disruption led to TCA cycle alterations, including α-ketoglutarate accumulation and succinyl-CoA reduction.
- Supplementation with succinate rescued DLST-inactivation-induced viability defects.
Conclusions:
- DLST plays a significant role in MYC-mediated leukemogenesis.
- T-lymphoblasts exhibit metabolic dependency on the TCA cycle.
- DLST and TCA cycle alterations present potential therapeutic targets for T-ALL.
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