Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice

Muto, Hideharu; Sakata‐Yanagimoto, Mamiko; Nagae, Genta; Shiozawa, Yusuke; Miyake, Yasuyuki; Yoshida, Kenichi; Enami, Terukazu; Kamada, Yuko; Kato, Takuya; Uchida, Katsuo; Nanmoku, Toru; Obara, Naoshi; Suzukawa, Kazumi; Sanada, Masashi; Nakamura, Naoya; Aburatani, Hiroyuki; Ogawa, Seishi; Chiba, Shigeru

doi:10.1038/bcj.2014.83

Cited by 84 publications

(77 citation statements)

References 52 publications

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“…Development of CMML-like disease has also been described in several reports [16,[25][26][27][28][29][30] These findings are thought to model, in part, myeloid malignancies in patients.…”

Section: Lessons From Mice With Modified or Deleted Tet2 Genementioning

confidence: 71%

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Dysregulation of TET2 in hematologic malignancies

Chiba

2016

Int J Hematol

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actively demethylated was for many years a central question in the quest to better understand epigenetic regulation. Until recently, however, it remained unsolved, with a history of failures in the discovery of DNA demethylases in animal cells [1]. In 2009, the ten-eleven translocation 1 (TET1) gene was shown to encode a dioxygenase that converts 5-mC to 5-hydroxymethylcytocine (5-hmC) by transferring an oxygen atom to the methyl group of 5-mC [2]. This discovery triggered the subsequent rapid progress in understanding the mechanisms that underlie demethylation processes [3,4]. TET2 and TET3 were soon found to be products of genes belonging to the same family as TET1 and to exhibit similar dioxygenase functions [5,6]. Once a TET dioxygenase catalyzes the 5-mC to 5-hmC conversion, multistep biochemical reactions follow, and the position is ultimately replaced by the unmodified cytosine (uC) (Fig. 1).Somatic TET2 mutations are frequently identified in a wide variety of hematologic malignancies [7,8]. These mutations cause impairment of enzymatic activity of the TET2 dioxygenase, resulting in the failure of 5-mC to 5-hmC conversion, and eventually failure of demethylation. The abnormal 5-mC/5-hmC/uC pattern in the TET2 mutation-carrying cells is thought to cause changes in the expression of the target genes and eventually drive the cells to develop hematologic malignancies. However, it remains unclear how TET2 mutations change the scheme of methyl group modification of the cytosine at the CpG sites throughout the genome and how such structural changes affect gene expression profiles.There have, however, been important advances in our understanding of why TET2 mutations are identified so commonly in such a wide variety of hematologic malignancies and the biological significance of these mutations. In this PIH article, I will focus mainly on the biological Abstract The TET dioxygenases, TET1, TET2, and TET3, catalyze transfer of an oxygen atom to the methyl group of 5-methylcytocine (5-mC), converting it to 5-hydroxymethylcytocine (5-hmC). Among the genes encoding these enzymes, ten-eleven translocation 2 (TET2) is frequently mutated somatically in both myeloid and lymphoid malignancies. Because these TET2 mutations result in the impairment of the dioxygenase activity of TET2, it is thought that these mutations interfere with 5-mC to 5-hmC conversion. There is ample evidence indicating that TET2 mutations are a driver of tumorigenesis in blood cells and that TET2 mutations are often acquired at the hematopoietic stem/early progenitor cell stage. In addition, TET2 is the second-most frequently mutated gene in clonal hematopoiesis in individuals with no apparent blood cancers, suggesting that while TET2 mutations alone are insufficient to cause hematologic malignancy, they represent an early event during tumorigenesis. A number of questions, including the precise target genome regions of TET2, and the importance of the balance of 5-mC and 5-hmC in the regulatory regions in transcriptional control, remain.

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“…Development of CMML-like disease has also been described in several reports [16,[25][26][27][28][29][30] These findings are thought to model, in part, myeloid malignancies in patients.…”

Section: Lessons From Mice With Modified or Deleted Tet2 Genementioning

confidence: 71%

“…Mice with knocked-down or conditionally knocked-out Tet2 have provided some additional insights into the effects of impaired TET2 function on hematopoietic cells [16,[25][26][27][28][29][30]. In general, these mice do not show evident abnormalities before reaching advanced age.…”

Section: Lessons From Mice With Modified or Deleted Tet2 Genementioning

confidence: 99%

Dysregulation of TET2 in hematologic malignancies

Chiba

2016

Int J Hematol

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“…Tet2 -deficient mouse models elicit altered T-cell differentiation and can develop T-cell lymphoma with T FH -like features [99,100]. In Tet2 -knockdown mice, the outgrowth of T FH -like tumor cells was connected to methylation changes of BCL-6 [100], the locus repressor of STAT5A/B .…”

Section: Targets In Ptcl and Driver Mutationsmentioning

confidence: 99%

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Orlova

Wingelhofer

Neubauer

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

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“…10,11 A highly recurrent dominant-negative G17V mutation in the RHOA GTPase was recently discovered in as much as 70% of AITL and TFH-like PTCLs. [12][13][14] RHOA is activated downstream of T-cell receptor (TCR) engagement in mature T cells and is linked to cytoskeleton reorganization after T-cell activation.…”

Section: Introductionmentioning

confidence: 99%