Dr. An-Ping Lin and Dr. Ricardo Aguiar

Evidence links lymphomas to flawed metabolism

Dr. An-Ping Lin and Dr. Ricardo Aguiar are the first and senior authors, respectively, of the manuscript that described the discovery of an unexpected role for the enzyme D2HGDH in human cancer.

Dr. An-Ping Lin and Dr. Ricardo Aguiar are the first and senior authors, respectively, of the manuscript that described the discovery of an unexpected role for the enzyme D2HGDH in human cancer.

School of Medicine researchers have found a direct link between disrupted metabolism and a common and often fatal type of lymphoma.

“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. He is a professor of medicine in the Division of Hematology and Medical Oncology and a faculty scientist with the Cancer Therapy & Research 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.”

The team, which included members of the 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.

crystal-structure“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.

The metabolite has been recently identified as a critical regulator of aging and stem cell maintenance, he said.

“The implications of our findings are broad and not limited to cancer biology,” he said.

The finding was announced in Nature Communications.

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