TET2: A cornerstone in normal and malignant hematopoiesis. Issue 1 (18th November 2020)

• Record Type: Journal Article
• Authors: Kunimoto, Hiroyoshi; Nakajima, Hideaki
• Is Part Of: Cancer science. Volume 112:Issue 1(2021)
• Page Start: 31
• Page End: 40
• Publication Date: 2020-11-18
• Subjects: cytosine demethylation -- hematological malignancy -- hematopoietic stem cell -- TET2; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14688
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Regulation of genome‐wide DNA methylation is fundamental for a variety of biological processes such as mammalian development, stem cell function, cellular proliferation/differentiation, and oncogenesis. Among the regulators of DNA methylation, ten‐eleven translocation 2 ( TET2 ) is one of the most frequently mutated genes in clonal hematopoiesis of indeterminate potential and in various hematological malignancies, underscoring a pivotal role for TET2 in blood homeostasis and hematopoietic transformation. TET2 oxidizes methylated cytosines to further modify cytosines, which behave as intermediates in active/passive DNA demethylation processes. TET2 itself associates with histone modifiers, thereby regulating histone modifications and expression of target genes. A number of studies have reported pleiotropic effects of TET2 on hematopoietic stem cell self‐renewal, hematopoietic differentiation, genome instability and inflammatory response. Recent single‐cell genomics studies have identified gene promoters as well as transcription factor binding sites as TET2‐targeted genetic loci in which disruption of DNA methylation can fundamentally modify hematopoietic differentiation and promote leukemogenesis. TET2 mutations show convergent cooperativity with other disease alleles in signaling molecules, epigenetic modifiers, and spliceosome factors in hematopoietic transformation. Future studies focusing on the molecular basis of stem cell and immune regulation by TET2 loss will further deepen our understanding of the entire landscape of pathophysiology and molecular vulnerabilities of TET2 ‐mutated hematological malignancies. Abstract : Ten‐eleven translocation 2 (TET2) is a critical molecule for DNA demethylation and is recurrently mutated in clonal hematopoiesis of indeterminate potential and in various hematological malignancies. Functional loss of TET2 leads to enhanced self‐renewal of hematopoietic stem cells (HSCs), myeloid‐skewed differentiation, genome instability, and resistance of HSCs to inflammatory stress. Recent studies have shown convergent cooperativity of TET2 mutation with other disease alleles in signaling, epigenetic modification, and RNA splicing in hematopoietic transformation.