PUBLICATION
The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis
- Authors
- Anderson, N.M., Li, D., Peng, H.L., Laroche, F.J., Mansour, M.R., Gjini, E., Aioub, M., Helman, D.J., Roderick, J.E., Cheng, T., Harrold, I., Samaha, Y., Meng, L., Amsterdam, A., Neuberg, D.S., Denton, T.T., Sanda, T., Kelliher, M.A., Singh, A., Look, A.T., Feng, H.
- ID
- ZDB-PUB-160216-7
- Date
- 2016
- Source
- Leukemia 30(6): 1365-74 (Journal)
- Registered Authors
- Aioub, Miriam, Amsterdam, Adam, Anderson, Nicole M., Feng, Hui, Gjini, Evisa, Harrold, Itrat, Look, A. Thomas, Mansour, Marc, Samaha, Yasmina, Sanda, Takaomi
- Keywords
- none
- MeSH Terms
-
- 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
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Proto-Oncogene Proteins c-myc/metabolism*
- Zebrafish
- PubMed
- 26876595 Full text @ Leukemia
Citation
Anderson, N.M., Li, D., Peng, H.L., Laroche, F.J., Mansour, M.R., Gjini, E., Aioub, M., Helman, D.J., Roderick, J.E., Cheng, T., Harrold, I., Samaha, Y., Meng, L., Amsterdam, A., Neuberg, D.S., Denton, T.T., Sanda, T., Kelliher, M.A., Singh, A., Look, A.T., Feng, H. (2016) The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia. 30(6):1365-74.
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 dehydrogenase complex (KGDHC), which converts α-ketoglutarate (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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping