A new study led by researchers at the University of Texas Health Science Center at San Antonio has revealed a link between a type of lymphoma and a metabolism disruption. The study was published in the journal Nature Communications and is entitled “D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2”.
Lymphoma refers to a cancer that affects immune cells called lymphocytes, a type of white blood cell that defends the body from infections. Patients with lymphoma may experience swelling of the lymph nodes, fever, night sweats, itching, loss of appetite, sudden weight loss and fatigue. Non-Hodgkin’s lymphoma corresponds to around 85% of all the lymphoma cases diagnosed, with diffuse large B-cell lymphoma (DLBCL) accounting for the most common type of non-Hodgkin’s lymphoma. DLBCL is an aggressive, fast-growing lymphoma that develops from a specific type of lymphocytes called B cells.
Metabolism (energy production) has been previously reported to be associated with cancer development. “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 the study’s senior author Dr. Ricardo C.T. Aguiar in a news release. In the study, researchers have now “discovered a metabolic imbalance that is oncogenic or pro-cancer,” stated Dr. Aguiar.
Researchers found that the gene encoding the enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated in DLBCL, which causes a deficiency in a compound called alpha-ketoglutarate (alpha-KG). Cells require steady levels of alpha-KG to maintain a healthy status as this factor can influence malignant behavior, longevity and stem cell maintenance. D2HGDH was found to contribute to the cellular pool of alpha-KG by regulating the activity of isocitrate dehydrogenases (IDH) in the mitochondria. IDH converts isocitrate into alpha-KG. In addition, “When the levels of alpha KG are abnormally low, another class of enzymes called dioxygenases don’t function properly, resulting in a host of additional disturbances,” explained Dr. Aguiar.
The research team concluded that the metabolic enzyme D2HGDH is linked to the capacity of cancer to regulate IDH2 activity and consequently alpha-KG production. The authors suggest that modulation of alpha-KG may be a relevant approach in cancer therapeutics.
The team believes that their findings have implications in the fields of cancer and metabolism, but also on other areas as alpha-KG has been recently reported to be involved in aging and stem cell maintenance. “Thus, the implications of our findings are broad and not limited to cancer biology,” concluded Dr. Aguiar.