<i>TET1</i>
            plays an essential oncogenic role in
            <i>MLL</i>
            -rearranged leukemia

Huang, Hao; Jiang, Xi; Li, Zejuan; Li, Yuanyuan; Song, Chun-Xiao; He, Chunjiang; Sun, Miao; Chen, Ping; Gurbuxani, Sandeep; Wang, Jiapeng; Hong, Gia Ming; Elkahloun, Abdel G.; Arnovitz, Stephen; Wang, Jinhua; Szulwach, Keith E.; Lin, Li; Street, Craig; Wunderlich, Mark; Dawlaty, Meelad M.; Neilly, Mary Beth; Jaenisch, Rudolf; Yang, Feng Chun; Mulloy, James C.; Jin, Peng; Liu, Paul P.; Rowley, Janet D.; Xu, Mingjiang; He, Chuan; Chen, Jianjun

doi:10.1073/pnas.1310656110

Cited by 197 publications

(217 citation statements)

References 59 publications

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“…Despite this, the role of TET proteins in cancer progression has been debated. Our findings presented here are linked with an oncogenic role for TET proteins; this is consistent with previous reports demonstrating that TET proteins are associated with prognostic epigenetic signature and the regulation for a set of important oncogenic targets (47,48). Reduced 5hmC level was found in some types of cancer as compared with corresponding normal tissue (49); however, the correlation of 5hmC level as well as the related enzyme-TET proteins with tumor grading in breast cancer has not been thoroughly dissected.…”

Section: Discussionsupporting

confidence: 93%

Hypoxia Drives Breast Tumor Malignancy through a TET–TNFα–p38–MAPK Signaling Axis

et al. 2015

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Hypoxia is a hallmark of solid tumors that drives malignant progression by altering epigenetic controls. In breast tumors, aberrant DNA methylation is a prevalent epigenetic feature associated with increased risk of metastasis and poor prognosis. However, the mechanism by which hypoxia alters DNA methylation or other epigenetic controls that promote breast malignancy remains poorly understood. We discovered that hypoxia deregulates TET1 and TET3, the enzymes that catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby leading to breast tumor-initiating cell (BTIC) properties. TET1/3 and 5hmC levels were closely associated with tumor hypoxia, tumor malignancy, and poor prognosis in breast cancer patients. Mechanistic investigations showed that hypoxia leads to genome-wide changes in DNA hydroxymethylation associated with upregulation of TNFa expression and activation of its downstream p38-MAPK effector pathway. Coordinate functions of TET1 and TET3 were also required to activate TNFa-p38-MAPK signaling as a response to hypoxia. Our results reveal how signal transduction through the TET-TNFa-p38-MAPK signaling axis is required for the acquisition of BTIC characteristics and tumorigenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy. Cancer Res; 75(18); 3912-24. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 93%

Hypoxia Drives Breast Tumor Malignancy through a TET–TNFα–p38–MAPK Signaling Axis

et al. 2015

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“…The chimeric protein lacks the hydroxylase activity, as the cys-rich domain of TET1 that is essential for enzymatic activity is deleted ). Interestingly, studies demonstrated that TET1 is overexpressed in MLL-rearranged leukemia and that TET1 function is required for up-regulating the expression of MLL chimera oncogenic targets such as HOXA9, MEIS1, and PBX3 (Huang et al 2013a). Reconciling this requirement for TET1 in MLL-rearranged leukemias and the molecular consequence of the MLL-TET1 rearrangement and its interplay with endogenous TET1 has yet to be determined.…”

Section: Dna Methylation In Hematopoiesis and Hematological Cancersmentioning

confidence: 99%

Epigenetics of hematopoiesis and hematological malignancies

Hu¹,

Shilatifard

2016

Genes Dev.

133

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Hematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms in which normal hematopoiesis has gone awry and together account for ∼10% of all new cancer cases diagnosed in the United States in 2016. Recent intensive genomic sequencing of hematopoietic malignancies has identified recurrent mutations in genes that encode regulators of chromatin structure and function, highlighting the central role that aberrant epigenetic regulation plays in the pathogenesis of these neoplasms. Deciphering the molecular mechanisms for how alterations in epigenetic modifiers, specifically histone and DNA methylases and demethylases, drive hematopoietic cancer could provide new avenues for developing novel targeted epigenetic therapies for treating hematological malignancies. Just as past studies of blood cancers led to pioneering discoveries relevant to other cancers, determining the contribution of epigenetic modifiers in hematologic cancers could also have a broader impact on our understanding of the pathogenesis of solid tumors in which these factors are mutated.

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“…These studies suggest that an unusual DNA methylation/demethylation dynamic may be attributable to the alteration of the epigenome and phenotype in leiomyoma. Interestingly, TET1 upregulation leading to a global increase in 5-hmC levels was also found in mixed lineage leukemia (MLL)-rearranged leukemia, 92 indicating that TET proteins may play an oncogenic role in certain tumors.…”

Section: Active Dna Demethylation In Uterine Leiomyomamentioning

confidence: 99%

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

et al. 2016

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Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and teneleven translocation protein 3-mediated elevated levels of 5-hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17b-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options.

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TET1 plays an essential oncogenic role in MLL -rearranged leukemia

Cited by 197 publications

References 59 publications

Hypoxia Drives Breast Tumor Malignancy through a TET–TNFα–p38–MAPK Signaling Axis

Hypoxia Drives Breast Tumor Malignancy through a TET–TNFα–p38–MAPK Signaling Axis

Epigenetics of hematopoiesis and hematological malignancies

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

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