The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis
| Autor: | Michelle A. Kelliher, A T Look, M Aioub, H.L. Peng, Y. Samaha, Evisa Gjini, Daniel Helman, Donna Neuberg, T Cheng, Marc R. Mansour, Itrat Harrold, Travis T. Denton, Adam Amsterdam, Dun Li, Takaomi Sanda, Justine E. Roderick, Nicole M. Anderson, Fabrice Laroche, Anurag K. Singh, Hui Feng, Le Meng |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Cell Survival Citric Acid Cycle Apoptosis Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma medicine.disease_cause Article Proto-Oncogene Proteins c-myc 03 medical and health sciences 0302 clinical medicine RNA interference Cell Line Tumor medicine Animals Humans Viability assay Zebrafish Gene knockdown Hematology biology.organism_classification Cell biology Citric acid cycle 030104 developmental biology Oncology Biochemistry Cell culture 030220 oncology & carcinogenesis Ketoglutaric Acids Acyl Coenzyme A Acyltransferases |
| Zdroj: | Leukemia. 30:1365-1374 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2016.26 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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