TET2 as an epigenetic master regulator for normal and malignant hematopoiesis

• Published in: Cancer science 2014-09, Vol.105 (9), p.1093-1099
• Main Authors: Nakajima, Hideaki, Kunimoto, Hiroyoshi
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Binding sites; Chromatin; Chromosomes; Cloning; Cytosine; Cytosine demethylation; Demethylation; Deoxyribonucleic acid; DNA; DNA Methylation; DNA-Binding Proteins - physiology; Epigenesis, Genetic; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic; Genetic transformation; Genomes; Hematologic Neoplasms - genetics; hematological malignancies; Hematology; Hematopoiesis - genetics; Hematopoietic stem cells; Homeostasis; Humans; Isocitrate dehydrogenase; Leukemia; Lymphoma; MicroRNAs; Mutation; Myelodysplastic syndrome; N-Acetylglucosamine; Proteins; Proto-Oncogene Proteins - physiology; Review; Stem cell transplantation; Stem cells; TET2; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12484

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. Ten‐eleven translocation (TET) family proteins are key enzyme for cytosine demethylation, and their second family member, TET2, is one of the frequently mutated genes in hematological malignancies. TET2 critically regulates HSC homeostasis and its functional impairment leads to expansion of premalignant clones. Therefore, TET2 is regarded as a epigenetic master regulator for normal and malignant hematopoiesis.