TET2 as an epigenetic master regulator for normal and malignant hematopoiesis

Abstract

DNA methylation is one of the critical epigenetic modifications regulating various cellular processes such as differentiation or proliferation, and its dysregulation leads to disordered stem cell function or cellular transformation. The ten-eleven translocation (TET) gene family, initially found as a chromosomal translocation partner in leukemia, turned out to be a key enzyme for DNA demethylation. TET genes hydroxylate 5-methylcytosine to 5-hydroxymethylcytosine, which is then converted to unmodified cytosine through multiple mechanisms. Somatic mutations of the TET2 gene were reported in a variety of human hematological malignancies such as leukemia, myelodysplastic syndrome, and malignant lymphoma, suggesting a critical role for TET2 in hematopoiesis. The importance of the TET-mediated cytosine demethylation pathway is also underscored by a recurrent mutation of isocitrate dehydrogenase 1 (IDH1) and IDH2 in hematological malignancies, whose mutation inhibits TET function through a novel oncometabolite, 2-hydroxyglutarate. Studies using mouse models revealed that TET2 is critical for the function of hematopoietic stem cells, and disruption of TET2 results in the expansion of multipotent as well as myeloid progenitors, leading to the accumulation of premalignant clones. In addition to cytosine demethylation, TET proteins are involved in chromatin modifications and other cellular processes through the interaction with O-linked β-N-acetylglucosamine transferase. In summary, TET2 is a critical regulator for hematopoietic stem cell homeostasis whose functional impairment leads to hematological malignancies. Future studies will uncover the whole picture of epigenetic and signaling networks wired with TET2, which will help to develop ways to intervene in cellular pathways dysregulated by TET2 mutations.

Loss of 5-hydroxymethylcytosine and intratumoral heterogeneity as an epigenomic hallmark of glioblastoma

“…Interestingly, we did not find a correlation of IDH1 mutations and 5hmC amount. As mutated IDH1 (R132H) leads to the production of 2HG, a competitive inhibitor of ten-eleven-translocation (TET) enzymes [31], our data emphasize that in IDH1 wild type, GBMs alternative oncogenic pathways are activated leading to the loss of 5hmC [32,33].…”

MBD3L2 promotes Tet2 enzymatic activity for mediating 5-methylcytosine oxidation

“…The Tet2-inactivating mutations in hematological malignancies and other solid tumors suggest that cellular transformation is in part caused by the dysregulation of 5mC conversion (Nakajima and Kunimoto, 2014). It has been suggested that downregulation of Tet2 is responsible for the loss of 5hmC in melanoma cells and overexpression of Tet2 suppresses melanoma growth, indicating that 5hmC regulated by Tet2 affects melanoma progression (Lian et al, 2012).…”

Mutations of myelodysplastic syndromes (MDS): An update

“…Its knockdown effects result in loss of 5hmC with a possible concomitant increase in 5-mC. TET2 is a crucial regulator of HSC-homeostasis [64]. TET2 mutations in MDS are thought to result in loss of catalytic activity.…”