Steven Grant, MD
Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468:839-843.
Dr. Grant indicated no relevant conflicts of interest.
Aberrant methylation of DNA, particularly hypermethylation of tumor suppressor genes, occurs frequently in many cancers, including hematopoietic malignancies. This has prompted the development of agents capable of reversing hypermethylation, such as DNA methyltransferase inhibitors. These agents have yielded encouraging results both alone and in combination with other epigenetic agents (e.g., histone deacetlyase inhibitors) in patients with myelodysplastic syndrome (MDS) and some acute leukemias. However, the endogenous factors regulating the hypermethylated state have not been fully elucidated.
The α-ketoglutarate-dependent TET2 gene is closely related to TET1, whose protein product is responsible for conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Somatic mutations in TET2 occur with significant frequency in patients with certain myeloid malignancies, including MDS, acute myeloid leukemia (AML), myeloproliferative neoplasms, and chronic myelomonocytic leukemia (CMML). Until recently, however, the physiologic implications of TET2 dysregulation and its relationship to DNA methylation patterns were unknown.
This has now changed, with a recent report by Dr. Ko and colleagues from Children’s Hospital Boston and Cleveland Clinic. The team of investigators characterized the functional implications of dysregulation of TET2 in myeloid malignancies in relation to hematopoietic cell behavior, DNA methylation patterns, and levels of 5hmC. They found that TET2 mutations were associated with low levels of 5hmC compared with healthy controls. Moreover, shRNA knockdown of TET2 in a murine model resulted in a pronounced shift toward monocytic/macrophage development. An unexpected finding was that TET2 dysregulation was associated with hypomethylation, rather than hypermethylation, of differentially regulated CpG islands. The authors concluded that TET2 plays an important role in normal myelopoiesis, and that a strong association exists between myeloid malignancies and the loss of TET2 catalytic function. They further proposed that levels of 5hmC in the cells of patients with myeloid malignancies may have independent prognostic significance and could potentially provide a basis for future targeted therapeutic interventions. Interestingly, in human AML, mutations in the citrate metabolism genes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have recently been shown to act in part by interfering with TET2 function.1
The results of these studies have a number of implications for myeloid malignancies. Although the clinical implications of TET2 mutations remain the subject of debate, diminished levels of 5hmC may nevertheless serve as a prognostic indicator in these disorders, particularly in circumstances in which epigenetic forms of therapy are employed. These studies also provide a possible link between genetic aberrations and the metabolic dysregulation characteristic of cancer cells. For example, mutations in metabolism-related genes such as IDH1/2 and TET2 may modify gene expression by altering DNA methylation patterns and, in doing so, could contribute to leukemic transformation. Although the relationships between these events will undoubtedly prove to be highly complex, further insights could lead to novel therapeutic paradigms and possibly more individualized treatments for patients with myeloid malignancies.
- Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553-567.