title: The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis.
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 (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.
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Anderson
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Division of Hematology/Institute of Molecular Hematology, Second Xiang-Ya Hospital, Central South University, Changsha, China.
authors.forename: H L
authors.initials: HL
authors.lastname: Peng
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: F J F
authors.initials: FJ
authors.lastname: Laroche
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Mansour
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Gjini
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Aioub
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Helman
authors.affiliation: Department of Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Roderick
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Harrold
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Samaha
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Meng
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Amsterdam
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Denton
authors.affiliation: Department of Medicine, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: T
authors.initials: T
authors.lastname: Sanda
authors.affiliation: Department of Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Kelliher
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Look
authors.affiliation: Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: H
authors.identifier: 0000-0003-1318-821X
authors.initials: H
authors.lastname: Feng
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000217:Acyltransferases / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002470:Cell Survival; D002952:Citric Acid Cycle; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D000214:Acyl Coenzyme A; D007656:Ketoglutaric Acids; D016271:Proto-Oncogene Proteins c-myc; C012046:succinyl-coenzyme A; D000217:Acyltransferases; C021515:dihydrolipoamide succinyltransferase