@article{9bc2563c4abf4e3a82063141882d667b,
title = "The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage",
abstract = "Cancer cells are metabolically similar to their corresponding normal tissues. Differences between cancers and normal tissues may reflect reprogramming during transformation or maintenance of the metabolism of the specific normal cell type that originated the cancer. Here, we compare glucose metabolism in hematopoiesis and leukemia. Thymus T cell progenitors were glucose avid and oxidized more glucose in the tricarboxylic acid cycle through pyruvate dehydrogenase (PDH) as compared with other hematopoietic cells. PDH deletion decreased double-positive T cell progenitor cells but had no effect on hematopoietic stem cells, myeloid progenitors, or other hematopoietic cells. PDH deletion blocked the development of Pten-deficient T cell leukemia, but not the development of a Pten-deficient myeloid neoplasm. Therefore, the requirement for PDH in leukemia reflected the metabolism of the normal cell of origin independently of the driver genetic lesion. PDH was required to prevent pyruvate accumulation and maintain glutathione levels and redox homeostasis.",
keywords = "T cell leukemia, double-positive thymocytes, glycolysis, hematopoietic stem cells, metabolism, pyruvate dehydrogenase, thymus",
author = "Sojeong Jun and Swetha Mahesula and Mathews, {Thomas P.} and Martin-Sandoval, {Misty S.} and Zhiyu Zhao and Elena Piskounova and Michalis Agathocleous",
note = "Funding Information: M.A. is a Cancer Prevention and Research Institute of Texas scholar and an American Society of Hematology faculty scholar. We thank S. Morrison and R. DeBerardinis for discussions and B. Harris for comments on the manuscript. We thank A. Tasdogan, B. Faubert, and J. Sudderth for help with glucose infusions and GC-MS analysis, and Y. Li for help with LC-MS analysis. We thank L. Nguyen, J. Rose III, and Q. Ding for mouse colony management; N. Loof and the Moody Foundation Flow Cytometry Facility for flow cytometry; and L. Zacharias, D. Do, and the CRI Metabolomics Facility for assistance with metabolomics. This work was supported by the Cancer Prevention and Research Institute of Texas ( RR180007 ), an “A” Award from Alex{\textquoteright}s Lemonade Stand Foundation for Childhood Cancer , and the American Society of Hematology Faculty Scholar Award . S.J. was in part supported by a fellowship from the Center for Regenerative Science and Medicine at UT Southwestern. Funding Information: M.A. is a Cancer Prevention and Research Institute of Texas scholar and an American Society of Hematology faculty scholar. We thank S. Morrison and R. DeBerardinis for discussions and B. Harris for comments on the manuscript. We thank A. Tasdogan, B. Faubert, and J. Sudderth for help with glucose infusions and GC-MS analysis, and Y. Li for help with LC-MS analysis. We thank L. Nguyen, J. Rose III, and Q. Ding for mouse colony management; N. Loof and the Moody Foundation Flow Cytometry Facility for flow cytometry; and L. Zacharias, D. Do, and the CRI Metabolomics Facility for assistance with metabolomics. This work was supported by the Cancer Prevention and Research Institute of Texas (RR180007), an ?A? Award from Alex's Lemonade Stand Foundation for Childhood Cancer, and the American Society of Hematology Faculty Scholar Award. S.J. was in part supported by a fellowship from the Center for Regenerative Science and Medicine at UT Southwestern. S.J. S.M. and M.A. designed and performed all experiments and analyzed all data. S.M. T.P.M. M.S.M.-S. and M.A. developed metabolomics methods. Z.Z. helped with statistical analysis. E.P. helped with histone acetylation experiments. M.A. wrote the manuscript with help from S.J. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = sep,
day = "7",
doi = "10.1016/j.cmet.2021.07.016",
language = "English (US)",
volume = "33",
pages = "1777--1792.e8",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "9",
}