Public Release:  Lymphomas tied to metabolic disruption

Evidence of enzyme deficiency found in these often-fatal cancers

University of Texas Health Science Center at San Antonio

SAN ANTONIO (July 17, 2015) -- Researchers from the School of Medicine at The University of Texas Health Science Center at San Antonio have found evidence that directly links disrupted metabolism (energy production in cells) to a common and often fatal type of lymphoma. The finding was announced Thursday (July 16) in Nature Communications.

"The link between metabolism and cancer has been proposed or inferred to exist for a long time, but what is more scarce is evidence for a direct connection -- genetic mutations in metabolic enzymes," said senior author Ricardo C.T. Aguiar, M.D., Ph.D., associate professor of hematology-oncology in the School of Medicine and a faculty scientist with the Cancer Therapy & Research Center (CTRC) at the UT Health Science Center and the South Texas Veterans Health Care System, Audie L. Murphy Division.

"We have discovered a metabolic imbalance that is oncogenic or pro-cancer," Dr. Aguiar said.

The team, which included members of the Health Science Center departments of medicine and biochemistry, investigators from the UT Southwestern Medical Center at Dallas and a group of collaborators from Austria, found that the gene that codes the enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated in a subset of cancers called diffuse large B-cell lymphomas. The mutated lymphoma cell displays a deficiency of a metabolite called alpha-ketoglutarate (α-KG), which is needed in steady levels for cells to be healthy.

"When the levels of α-KG are abnormally low, another class of enzymes called dioxygenases don't function properly, resulting in a host of additional disturbances," Dr. Aguiar said.

Dr. Aguiar indicated that α-KG has been recently identified as a critical regulator of aging and stem cell maintenance. "Thus, the implications of our findings are broad and not limited to cancer biology," he said.

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This research is supported in large part by the Cancer Prevention & Research Institute of Texas. Support of core facilities was provided by the CTRC Cancer Center support grant from the National Cancer Institute as well as the Institute for Integration of Medicine & Science, which administers the Clinical and Translational Science Award (CTSA) of the UT Health Science Center and its South Texas partners. The CTSA grant is from the National Center for Advancing Translational Sciences of the National Institutes of Health.

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The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio is one of the elite academic cancer centers in the country to be named a National Cancer Institute (NCI) Designated Cancer Center, and is one of only four in Texas. A leader in developing new drugs to treat cancer, the CTRC Institute for Drug Development (IDD) conducts one of the largest oncology Phase I clinical drug programs in the world, and participates in development of cancer drugs approved by the U.S. Food & Drug Administration. For more information, visit http://www.ctrc.net.

Article citation:

Nature Communications, July, 2015. 10.1038/ncomms8768

D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

An-Ping Lin 1, Saman Abbas 1, Sang-Woo Kim 1 †, Manoela Ortega 1, Hakim Bouamar 1, Yissela Escobedo 1, Prakash Varadarajan 1, Yuejuan Qin 1, Jessica Sudderth 2, Eduard Schulz 3, Alexander Deutsch 3, Sumitra Mohan 4, Peter Ulz 4, Peter Neumeister 3, Dinesh Rakheja 2,5, Xiaoli Gao 6, Andrew Hinck 6, Susan T. Weintraub 6, Ralph J. DeBerardinis 2, Heinz Sill 3, Patricia L. M. Dahia 1,7,8, Ricardo C. T. Aguiar 1,7,8,9

1 Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. 2 Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA. 3 Division of Hematology, Medical University of Graz, A-8036 Graz, Austria. 4 Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria. 5 Department of Pathology and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. 6 Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. 7 Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. 8 Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. 9 South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, Texas 78229, USA. † Present address: Department of Biological Sciences, Pusan National University, 63 Beon-gil 2, Busandaehag-ro, Geumjeong-gu, Pusan 609 735, Republic of Korea. Correspondence and requests for materials should be addressed to R.C.T.A. (email: aguiarr@uthscsa.edu).

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