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Transcriptional control and signal transduction, cell cycle

The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis

Leukemia volume 30, pages 1365–1374 (2016)Cite this article

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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.

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Acknowledgements

We thank John Gilbert and Joseph Hirsch for editorial assistance; Nicholas Nagykery and Lu Zhang for technical assistance; Bethany M. Moore, Trevor Grant, Dr Nicolay Brandon, Dr Adam Lerner, Dr Enxuan Jing, Dr Arthur JL Cooper, Dr Gromoslaw Smolen and Dr Keith Tornheim for helpful discussions and critical review of the manuscript; and Julia Etchin for reagents. We also thank Gregory Molind, John Lyons and Derek Walsh for zebrafish husbandry. HF was supported by a K99CA134743/R00CA134743 award (National Institute of Health), a Karin Grunebaum faculty fellowship from the Karin Grunebaum Cancer Foundation, a Ralph Edwards Career Development Professorship from Boston University, a St Baldrick Scholar Award from the St Baldrick's Foundation, an Institutional grant (IRG –72-001-36-IRG) from the American Cancer Society and a Young Investigator grant from the Leukemia Research Foundation. ATL receives funding support from a 1R01 CA176746 grant (National Institute of Health). IH and DL acknowledge support through a NHLB1 T32 HL007501 training grant. HLP receives support from a NSFC 81200368 grant. The content of this research is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author contributions

NMA and HF designed and performed experiments and wrote the manuscript; DL, FJL, HLP, MA, EG, TC, DJH, IH, YS and ML performed experiments; MRS, TS, AA, TTD and AS provided intellectual input to the project and experiments; JER and MAK provided patient samples from murine xenografts. DSN checked statistical analysis and provided intellectual input; ATL and HF supervised the project.

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Authors and Affiliations

  1. Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA

    N M Anderson, D Li, F J F Laroche, M Aioub, T Cheng, I Harrold, Y Samaha, L Meng, A Singh & H Feng

  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    H L Peng, M R Mansour, E Gjini, D J Helman & A T Look

  3. Division of Hematology/Institute of Molecular Hematology, Second Xiang-Ya Hospital, Central South University, Changsha, China

    H L Peng

  4. Department of Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA

    J E Roderick & M A Kelliher

  5. David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    A Amsterdam

  6. Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    D S Neuberg

  7. Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA, USA

    T T Denton

  8. Department of Medicine, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    T Sanda

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Correspondence to H Feng.

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Anderson, N., Li, D., Peng, H. et al. The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia 30, 1365–1374 (2016). https://doi.org/10.1038/leu.2016.26

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