In 2008, two research groups in Europe made an intriguing discovery: A significant number of people with leukemias carry a mutation in a gene called TET2. However, it was not clear how TET2 mutations contribute to the disease or how TET2 functions in healthy cells. Now a study led by researchers at Memorial Sloan-Kettering Cancer Center and New York University has shown that TET2 loss enhances the function of blood stem cells, causing them to renew themselves more efficiently than normal blood stem cells. These mutant cells outcompete the normal cells, a condition that progresses to leukemia.
The finding, published in the July issue of Cancer Cell, provides a key insight into what initially goes wrong in the development of many leukemias. [PubMed Abstract] “For the first time, we have definitive proof for what a TET2 mutation by itself does to the blood cells,” says medical oncologist Ross L. Levine, a member of the Human Oncology Pathogenesis Program and the Leukemia Service at Memorial Sloan-Kettering, who led the study along with Iannis Aifantis of the NYU Cancer Institute. “After proving TET2 loss confers a new capacity on the stem cells, we can start investigating whether existing or novel therapies might block that effect.”
Critical to the discovery was the development of a mouse model that lacks TET2 function in blood cells — the same cells that become cancerous in leukemia. The loss of TET2 in the animals had two dramatic effects: The blood stem cells had enhanced reproductive capabilities, and the mice went on to develop myeloid leukemia within six months. “These mice will serve as a valuable research tool allowing us to look for therapeutic targets that might be effective against leukemias caused by the TET2 mutation,” Dr. Levine says.
The Cancer Cell study is one of several recently published that shed light on how certain mutations may contribute to leukemia by modifying DNA methylation — a mechanism that allows a cell to chemically modify its genes leading to changes in gene expression. A related gene, TET1, was recently found to affect DNA methylation, and the researchers suspect TET2 has a similar function. There already are cancer drugs in clinical testing that target methylation, so such therapies might be effective against leukemia.