TET2 as an epigenetic master regulator for normal and malignant hematopoiesis. Issue 9 (3rd September 2014)

• Record Type: Journal Article
• Authors: Nakajima, Hideaki; Kunimoto, Hiroyoshi
• Is Part Of: Cancer science. Volume 105:Issue 9(2014:Sep.)
• Page Start: 1093
• Page End: 1099
• Publication Date: 2014-09-03
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12484
• Languages: English
• ISSNs: 1347-9032

Abstract

<abstract abstract-type="main" id="cas12484-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 (<italic>TET</italic>) gene family, initially found as a chromosomal translocation partner in leukemia, turned out to be a key enzyme for DNA demethylation. <italic>TET</italic> genes hydroxylate 5‐methylcytosine to 5‐hydroxymethylcytosine, which is then converted to unmodified cytosine through multiple mechanisms. Somatic mutations of the <italic>TET2</italic> gene were reported in a variety of human hematological malignancies such as leukemia, myelodysplastic syndrome, and malignant lymphoma, suggesting a critical role for <italic>TET2</italic> in hematopoiesis. The importance of the TET‐mediated cytosine demethylation pathway is also underscored by a recurrent mutation of isocitrate dehydrogenase 1 (<italic>IDH1</italic>) and <italic>IDH2</italic> in hematological malignancies, whose mutation inhibits TET function through a novel oncometabolite, 2‐hydroxyglutarate. Studies using mouse models revealed that <italic>TET2</italic> is critical for the function of hematopoietic stem cells, and disruption of <italic>TET2</italic> 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 <italic>O</italic>‐linked β‐<italic>N</italic>‐acetylglucosamine transferase. In summary, <italic>TET2</italic> 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 <italic>TET2</italic>, which will help to develop ways to intervene in cellular pathways dysregulated by <italic>TET2</italic> mutations.</p> </abstract>