TET1 is a tumor suppressor of hematopoietic malignancy

Cimmino, Luisa; Dawlaty, Meelad M.; Ndiaye‐Lobry, Delphine; Yap, Yoon Sing; Bakogianni, Sofia; Yu, Yiting; Bhattacharyya, Sanchari; Shaknovich, Rita; Geng, Huimin; Lobry, Camille; Mullenders, Jasper; King, Bryan; Trimarchi, Thomas; Aranda-Orgillés, Beatriz; Liu, Cynthia; Shen, Steven S.; Verma, Amit; Jaenisch, Rudolf; Aifantis, Iannis

doi:10.1038/ni.3148

Cited by 184 publications

(251 citation statements)

References 59 publications

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“…It was reported that the loss of Tet1 or Tet2 led to hematologic cancers (37,60,61), which are associated with low levels of 5hmC in genomic DNA (62). These results suggest that the defect in vitamin C metabolism might also be involved in cancer development or exacerbate the progression of cancers having Tet mutations.…”

Section: Discussionmentioning

confidence: 95%

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

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Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-β (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2−/− iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2−/− mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.

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Section: Discussionmentioning

confidence: 95%

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

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“…Besides underscoring nonredundant roles for ten-eleven translocation (TET) proteins in normal hematopoiesis and transformation, this reinforces a general function of TET(s) and DNA-methylation control as a tumor suppressor of B-cell malignancies. 13,44 A specific role of Tet3 in the B-cell lineage needs to be identified, however, because Tet3 inactivation does not markedly alter lymphopoiesis in mice (Ko et al 45 and our unpublished results).…”

Section: Discussionmentioning

confidence: 99%

“…8 However, no major member of the DNA methylation control pathway was recurrently found mutated in CLL and malignant B-cell differentiation. [12][13][14][15][16] Another player in B-cell malignant development is the activationinduced cytidine deaminase (AID) gene, which encodes a cytidine deaminase and is known to initiate both class switch recombination and somatic hypermutation, 2 main mechanisms implicated in the maturation of the antibody response. AID expression is tightly regulated, and its aberrant activity has been shown to induce mutations in nonimmunoglobulin genes, thus contributing to cellular transformation.…”

Section: Introductionmentioning

confidence: 99%

B-cell tumor development in Tet2-deficient mice

et al. 2018

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Key Points• Tet2 is a tumor suppressor in B cells.• Loss of Tet2 in B cells leads to age-dependent transformation that requires AID.The TET2 gene encodes an a-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B-and Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish thatTet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling.

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“…Specifically, Tet1-deficient mice on a mixed 129/Sv × C57BL/6 background produce normal-sized litters (10), but display minor behavioral abnormalities and defects in learning, memory, and expression of neuronal activation-related genes (11,12), as well as a tendency to develop B-cell lymphomas relatively late in life (13). Tet2-deficient mice on a pure C57BL/6 background are also viable and fertile; they exhibit mild hematopoietic phenotypes and occasionally develop myeloid malignancies late in life (14,15).…”

mentioning

confidence: 99%

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

Yue

Pastor

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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TET-family dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and oxidized methylcytosines in DNA. Here, we show that mouse embryonic stem cells (mESCs), either lacking Tet3 alone or with triple deficiency of Tet1/2/3, displayed impaired adoption of neural cell fate and concomitantly skewed toward cardiac mesodermal fate. Conversely, ectopic expression of Tet3 enhanced neural differentiation and limited cardiac mesoderm specification. Genome-wide analyses showed that Tet3 mediates cell-fate decisions by inhibiting Wnt signaling, partly through promoter demethylation and transcriptional activation of the Wnt inhibitor secreted frizzled-related protein 4 (Sfrp4). Tet1/2/3-deficient embryos (embryonic day 8.0–8.5) showed hyperactivated Wnt signaling, as well as aberrant differentiation of bipotent neuromesodermal progenitors (NMPs) into mesoderm at the expense of neuroectoderm. Our data demonstrate a key role for TET proteins in modulating Wnt signaling and establishing the proper balance between neural and mesodermal cell fate determination in mouse embryos and ESCs.

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TET1 is a tumor suppressor of hematopoietic malignancy

Cited by 184 publications

References 59 publications

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

B-cell tumor development in Tet2-deficient mice

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

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