Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice

Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M.; Pan, Feng; Weeks, Ophelia; Zhou, Yuan; Cao, Zhen-Dong; Shi, Hui; Wang, Jiapeng; Lin, Li; Chen, Shi; Yuan, Weiping; Qin, Zhaohui S.; Ni, Hongyu; Nimer, Stephen D.; Yang, Feng Chun; Jaenisch, Rudolf; Jin, Peng; Xu, Mingjiang

doi:10.1016/j.celrep.2015.10.037

Cited by 92 publications

(91 citation statements)

References 38 publications

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“…Furthermore, studies from two independent groups have shown that combination of Tet2 loss and Jak2V617F resulted in aggressive MPN phenotype through both clonal HSC dominance and expansion of downstream precursor populations [76,77]. Notably, TET2 mutations also cooccur with changes in other TET members or DNMT3A mutations in human acute B-lymphocytic leukemia and T-cell lymphoma [78,79]. Concordant with this, Tet1/2 double-knockout mice developed lethal B-cell malignancies, and Tet2 loss combined with Dnmt3a mutation caused T-cell lymphoma/leukemia in vivo, possibly owing to dysregulated Bcl6/Myc and Notch pathway, respectively [78,80,81].…”

Section: Tet2mentioning

confidence: 99%

“…Notably, TET2 mutations also cooccur with changes in other TET members or DNMT3A mutations in human acute B-lymphocytic leukemia and T-cell lymphoma [78,79]. Concordant with this, Tet1/2 double-knockout mice developed lethal B-cell malignancies, and Tet2 loss combined with Dnmt3a mutation caused T-cell lymphoma/leukemia in vivo, possibly owing to dysregulated Bcl6/Myc and Notch pathway, respectively [78,80,81]. Collectively, these data suggest that functional convergent cooperativity of TET2 mutations and co-occurring disease alleles drives hematopoietic transformation.…”

Section: Tet2mentioning

confidence: 99%

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Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

Kunimoto

Nakajima

2017

Int J Hematol

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Section: Tet2mentioning

confidence: 99%

Section: Tet2mentioning

confidence: 99%

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

Kunimoto

Nakajima

2017

Int J Hematol

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“…This may indicate a neutral effect on B cells. Nevertheless, the development of B-cell acute lymphoblastic leukemia was recently reported in mice with double deletion of Tet1 and Tet2 [33].…”

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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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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“…understood, particularly as conditional knockout (KO) of TET1, TET1/2 or TET2/3 in murine hematopoietic cells has profound biological consequences [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Roles of IDH1/2 and TET2 mutations in myeloid disorders

2016

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Although mutated IDH1/2 are clearly established as oncogenes in myeloid cells, the mechanisms underlying their tumorigenic effects are not clear. Much evidence suggests that mutant IDH enzymes exert their effects via inhibition of TET2, but important clinical differences between IDH1-mutant and TET2-mutant hematopoietic disorders suggest that the oncogenic mechanisms of these mutated enzymes may differ. In particular, divergent effects of mutant IDH1/2 and TET2 on DNA damage repair mechanisms have been identified. In this review, we examine mutant IDH1/2 and TET2 in the context of responses to DNA damage and their potential involvement in genomic instability. We also discuss the clinical relevance of these findings and their potential application in novel therapeutic strategies. Mutation of TET family enzymesThe TET family of dioxygenases is highly conserved and contains three members: TET1, -2 and -3. Somatic mutations of TET2 occur in various myeloid disorders, including chronic myelomonocytic leukemia (CMML) (~50 %), myeloid proliferative neoplasm (MPN) (~13 %), MDS (~25 %) and AML (~23 %) [1,2]. TET2 is also mutated in B and T cell lymphoid malignancies, including angioimmunoblastic T cell lymphoma (AITL) [3]. More recently, TET2 mutations have been detected in elderly individuals with clonal hematopoiesis of indeterminate potential, i.e.: individuals with clonal hematopoiesis without identified hematological disease. This indicates that TET2 mutations alone cannot drive leukemogenesis and that additional events probably contribute [4,5]. Interestingly, TET1 and TET3 mutations are rare in human hematological diseases [6]. This predominance of TET2 alterations is not Abstract Mutations of the epigenetic enzymes isocitrate dehydrogenase (IDH) 1 and 2, and the methylcytosine dioxygenase 'ten-eleven translocation 2' (TET2), are common in human myeloid malignancies and drivers of these disorders but the underlying mechanisms remain obscure. This review examines mutant IDH1/2 and TET2 enzymes in the context of responses to DNA damage and their potential involvement in age-related genomic instability. The clinical relevance of these findings and their potential application in novel therapeutic strategies is also discussed.

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Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice

Cited by 92 publications

References 38 publications

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

Dysregulation of TET2 in hematologic malignancies

Roles of IDH1/2 and TET2 mutations in myeloid disorders

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