Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid Transformation

Moran-Crusio, Kelly; Reavie, Linsey B.; Shih, Alan H.; Abdel-Wahab, Omar; Ndiaye‐Lobry, Delphine; Lobry, Camille; Figueroa, María E.; Vasanthakumar, Aparna; Patel, Jay P.; Zhao, Xinyang; Perna, Fabiana; Pandey, Suveg; Madžo, Jozef; Song, Chun-Xiao; Dai, Qing; He, Chuan; Ibrahim, Sherif; Beran, Miloslav; Zavadil, Jiří; Nimer, Stephen D.; Melnick, Ari; Godley, Lucy A.; Aifantis, Iannis; Levine, Ross L.

doi:10.1016/j.ccr.2011.06.001

Cited by 1,178 publications

(1,193 citation statements)

References 41 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: 94%

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: 94%

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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“…To confirm that somatic gene mutations prime HSPCs for pyroptosis in MDSs, we performed comparative analyses of published gene expression profiles from human and murine SRSF2 (GSE65349) and U2AF1 mutants (GSE30195 and GSE66793) vs WT, TET2 knockout (GSE27816), and primary MDS (GSE19429) vs normal HSPCs and found uniform upregulation of pyroptosis effectors, consistent with transcriptional priming. [39][40][41][42][43] Importantly, in MDS BM specimens, BM plasma concentration of S100A9 positively correlated with NLRP3 MFI, percentage and MFI of plasma ASC specks, and the presence of SGMs and variant allele frequency (supplemental Figure 8). Furthermore, both the percentage and MFI of plasma ASC specks were significantly increased in MDS patients harboring SGMs (supplemental Figure 8D-E).…”

Section: Org Frommentioning

confidence: 99%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

295

350

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Key Points• Key biological features of MDSs are explained by NLRP3 inflammasome activation, which drives pyroptotic cell death and b-catenin activation.• Alarmin signals and founder gene mutations license this redox-sensitive inflammasome platform.Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1b (IL-1b) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and b-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear b-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention. (Blood. 2016;128(25):2960-2975

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“…17 Mouse models have demonstrated that Tet2 deficiency endows the cell with growth advantage over wild-type cells and have suggested that the development of a full-blown malignancy depends on the occurrence of additional mutations. 8,18,19 In our previously published Tet2-deficient models, a fraction (;30%) of aging animals develops a chronic myelomonocytic leukemia-like disease, whereas another third shows the accumulation of an abnormal B-cell population characterized by a low level of B220 at the cell surface (B220 low B cells). 8 Here, we report the analyses of the B-cell differentiation and B-cell malignancy development in both constitutive and B-cell-specific (CD19-Cre) Tet2-deficient mice.…”

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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Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid Transformation

Cited by 1,178 publications

References 41 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

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

B-cell tumor development in Tet2-deficient mice

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