The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases

• Published in: Leukemia Vol. 28; no. 3; pp. 485 - 496
• Main Authors: Solary, E, Bernard, O A, Tefferi, A, Fuks, F, Vainchenker, W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2014; Nature Publishing Group
• Subjects: 631/208/176/1988; 692/420/2489/2487/2486; 692/699/67/1990; Aging - genetics; Ascorbic acid; Ascorbic Acid - metabolism; Cancer Research; Cell differentiation; Cell self-renewal; Chromatin; Critical Care Medicine; Cytosine; Demethylation; Deoxyribonucleic acid; Development and progression; DNA; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryonic Stem Cells - metabolism; Epigenesis, Genetic; Epigenetics; Gene deletion; Gene expression; Gene mutations; Genes, Tumor Suppressor; Genetic aspects; Haploinsufficiency; Hematologic Diseases - genetics; Hematology; Hematopoiesis; Hematopoiesis - genetics; Hematopoietic stem cell disorders; Hematopoietic stem cells; Histones; Humans; Hydroxylase; Identification and classification; Inactivation; Intensive; Internal Medicine; Iron; Isocitrate dehydrogenase; Ketoglutaric acid; Medicine; Medicine & Public Health; MicroRNAs - physiology; miRNA; Monocytes; Mutation; N-Acetylglucosamine; Oncology; Point mutation; Post-transcription; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Ribonucleic acid; RNA; spotlight-review; Stem cells; Translocation; Translocation (Genetics); Tumor suppressor genes; Tumors; France; TET2; DNA methylation; dioxygenase; differentiation; stem cell; epigenetics
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2013.337

Ten-Eleven Translocation-2 ( TET2 ) inactivation through loss-of-function mutation, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutation is a common event in myeloid and lymphoid malignancies. TET2 gene mutations similar to those observed in myeloid and lymphoid malignancies also accumulate with age in otherwise healthy subjects with clonal hematopoiesis. TET2 is one of the three proteins of the TET (Ten-Eleven Translocation) family, which are evolutionarily conserved dioxygenases that catalyze the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promote DNA demethylation. TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which is enhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in the hematopoietic tissue, especially in hematopoietic stem cells. In addition to their hydroxylase activity, TET proteins recruit the O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) enzyme to chromatin, which promotes post-transcriptional modifications of histones and facilitates gene expression. The TET2 level is regulated by interaction with IDAX, originating from TET2 gene fission during evolution, and by the microRNA miR-22. TET2 has pleiotropic roles during hematopoiesis, including stem-cell self-renewal, lineage commitment and terminal differentiation of monocytes. Analysis of Tet2 knockout mice, which are viable and fertile, demonstrated that Tet2 functions as a tumor suppressor whose haploinsufficiency initiates myeloid and lymphoid transformations. This review summarizes the recently identified TET2 physiological and pathological functions and discusses how this knowledge influences our therapeutic approaches in hematological malignancies and possibly other tumor types.