In previous research, mutations in the TET2 (Ten-Eleven Translocation-2) gene were found across a broad range of myeloid malignancies, but little is known about the pathologic consequences of this mutation or the role it plays in the development of diseases such as myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia.

A team of scientists at the Taussig Cancer Institute at the Cleveland Clinic in Ohio and Dana-Farber Cancer Institute at Harvard University initiated several specialized experiments on leukemic cancer cells carrying TET2 gene mutations. TET2 mutations occurred throughout the entire TET2 gene and led to its inactivation. Functional studies showed that the TET2 mutations likely alter epigenetic regulation.

Epigenetic alterations are a form of chemical modification of the DNA strand that naturally occurs during normal tissue maturation, but is disturbed in cancer. One key epigenetic mechanism is the methylation of cytosines (one of the four building blocks of DNA), which effectively blocks or “silences” particular genes.

Experimental results demonstrate that the TET2 gene alters the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, which likely in turn affects the silencing function of 5- methylcytosine. TET2 mutations, or experimentally decreased TET2 levels, resulted in lower hydroxymethylcytosine levels and perturbed maturation of bone marrow stem cells.

“The process of methylation or ‘silencing’ of genes can be altered in disease or through application of epigenetic drugs. Identification of the variant of cytosine, 5-hydroxymethylcytosine, introduces a new mechanism of epigenetic regulation that has never been explored,” said senior study author Jaroslaw P. Maciejewski, MD, PhD, FACP, Chairman, Department of Translational Hematology and Oncology Research, Taussig Cancer Institute at the Cleveland Clinic in Ohio. “The mutation in TET2 is an important, common mutation associated with leukemia that affects epigenetics, and now we are closer to deciphering the functional consequences of this mutation. It is likely that 5-hydroxymethylcytosine levels may become a disease biomarker and possibly molecular target for the development of new therapies.”