TET2 Mutation May Play Role in Development of Acute Myeloid Leukemia

Roxanne Nelson

December 07, 2010

December 7, 2010 — Deletions or mutations in the TET2 (Ten-Eleven Translocation 2) gene have been identified in a wide range of myeloid malignancies. However, the pathologic consequences of this mutation are unclear, and little is known about the role it plays in diseases such as myelodysplastic syndrome and acute myeloid leukemia.

Researchers have now found strong evidence that TET2 is involved in the conversion of 5-methylcytosine to 5-hydroxymethylcytosine in DNA. Thus, it appears to have a novel role in a substantial component of epigenetic deregulation in myeloid malignancies.

The findings were presented during the plenary session here at the American Society of Hematology 52nd Annual Meeting.

The measurement of 5-hydroxymethylcytosine might be a useful diagnostic and prognostic tool, and might help to individualize therapies and assess responses to treatment, explained senior author Jaroslaw P. Maciejewski, MD, PhD, FACP, chair of the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute at the Cleveland Clinic in Ohio. "It is likely that 5-hydroxymethylcytosine levels may become a disease biomarker and possibly a molecular target for the development of new therapies."

Mutations occur throughout the entire TET2 gene, leading to its inactivation. Studies have shown that the TET2 mutations likely alter epigenetic regulation, according to Dr. Maciejewski. Epigenetic alterations are a form of chemical modification of the DNA strand that naturally occur during normal tissue maturation but are disturbed in cancer. A key epigenetic mechanism is the methylation of cytosines, which effectively blocks specific genes.

"The significance of understanding the biology of cancer — and in our specific application of leukemia — is such that we now know the changes in DNA mutations and chromosomal breaks," he said at a press briefing held in advance of the presentation. "And we now know that we have epigenetic changes."

In this setting, the gene, which is mutated, is incapable of converting 5-methylcytosine to 5-hydroxymethylcytosine, and therefore the signaling processes are disturbed, explained Dr. Maciejewski. Future work in this area will identify specific genes and specific targets.

It will have a significant impact on what we will be able to do in the future diagnostically and therapeutically.

"Once we know what the function of the gene is, and the upstream and downstream partners of this particular chemical or biochemical pathway, we may be able to develop drugs to target this particular dysfunction," he pointed out. "The nice thing about it is that this gene has been predominant, so we assume by the frequency of this mutation that it will have a significant impact on what we will be able to do in the future diagnostically and therapeutically."

The implications are profound.

Peter Emanuel, MD, who served as moderator of the session, emphasized that "while this study may be difficult to understand, the implications are profound."

"The implications are not only for hematological malignancies, but all cancers in general," said Dr. Emanuel, who is from the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences in Little Rock.

The Philadelphia chromosome and the subsequent BCR-ABL was the first genetic mutation found in any cancer; it was discovered in 1960, he added. "As far as cancers go, [chronic myeloid leukemia] is a relatively simple cancer, as opposed to other malignancies. This study gets into the much more complex issues of other genetic mutations and their relationship to diseases that aren't so easy to find."

American Society of Hematology (ASH) 52nd Annual Meeting: Abstract 1. Presented December 6, 2010.

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