Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia

Jiang, Xi; Hu, Chao; Ferchen, Kyle; Nie, Ji; Cui, Xiaolong; Chen, Chih-Hong; Cheng, Liao‐Ping; Zuo, Zhixiang; Seibel, William; He, Chunjiang; Tang, Yixuan; Skibbe, Jennifer R.; Wunderlich, Mark; Reinhold, William C.; Dong, Lei; Shen, Chao; Arnovitz, Stephen; Ulrich, Bryan C.; Lu, Jiuwei; Weng, Hengyou; Su, Rui; Huang, He; Wang, Yungui; Li, Chenying; Qin, Xi; Mulloy, James C.; Zheng, Yi; Diao, Jiajie; Jin, Jie; Li, Chong; Liu, Paul P.; He, Chuan; Chen, Yuan; Chen, Jianjun

doi:10.1038/s41467-017-02290-w

Cited by 54 publications

(46 citation statements)

References 66 publications

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“…However, in some diseased states, the longer TET1 isoform is also expressed, regulated by additional mostly unidentified factors through the distal upstream promoter. This has been shown to include via activation of STAT3 and STAT5, which drive TET1 expression in AML, providing a possible target for treatment (Jiang et al, 2017 ). Expression of the short isoform is also regulated through a distal enhancer which encompasses one of the regions described as an alternative TSSs in ESCs (Sohni et al, 2015 ), and in the gonadotropes this region is protected from methylation by TET2 (Yosefzon et al, 2017 ).…”

Section: Different Mechanisms Of Regulating Tet Expression Give Rise mentioning

confidence: 99%

Tet Enzymes, Variants, and Differential Effects on Function

Melamed

Yosefzon

David

et al. 2018

Front. Cell Dev. Biol.

103

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Discovery of the ten-eleven translocation 1 (TET) methylcytosine dioxygenase family of enzymes, nearly 10 years ago, heralded a major breakthrough in understanding the epigenetic modifications of DNA. Initially described as catalyzing the oxidation of methyl cytosine (5mC) to hydroxymethyl cytosine (5hmC), it is now clear that these enzymes can also catalyze additional reactions leading to active DNA demethylation. The association of TET enzymes, as well as the 5hmC, with active regulatory regions of the genome has been studied extensively in embryonic stem cells, although these enzymes are expressed widely also in differentiated tissues. However, TET1 and TET3 are found as various isoforms, as a result of utilizing alternative regulatory regions in distinct tissues. Some of these isoforms, like TET2, lack the CXXC domain which probably has major implications on their recruitment to specific loci in the genome, while in certain contexts TET1 is seen paradoxically to repress transcription. In this review we bring together these novel aspects of the differential regulation of these Tet isoforms and the likely consequences on their activity.

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Section: Different Mechanisms Of Regulating Tet Expression Give Rise mentioning

confidence: 99%

Tet Enzymes, Variants, and Differential Effects on Function

Melamed

Yosefzon

David

et al. 2018

Front. Cell Dev. Biol.

103

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“…It has been reported that Tet1 alternative splicing forms have distinct functions [74]. However, the information regarding the Tet1 alternative splicing is still limited.…”

Section: Discussionmentioning

confidence: 99%

“…Alternative splicing mechanism leads to several TET1 isoforms, including the full-length canonical and the short transcripts [69][70][71][72][73]. TET1 expression is regulated by very complicated factors including the reprogramming factors such as Oct3/4, Nanog, and Myc [68,70] in early embryos, ESCs and PGCs [69], the transcription factors in the differentiated cells, and STAT3/STAT5 in acute myeloid leukemia (AML) [74].…”

Section: Tet1 and Regulation Of Its Target Gene Expressionmentioning

confidence: 99%

“…TET1 functions as an important oncoprotein in acute myeloid leukemia (AML) as evidenced by the high level expression of TET1 in AML, indicating that efficient inhibition of TET1 expression could serve as a powerful strategy for AML therapy. Drug screening led to identification of two compounds NSC-370284 and its structure analogue UC-514321, which repress TET1 transcription by targeting directly to target STAT3/5, TET1 transcriptional activators, suggesting the potential of the compounds targeting the STAT/TET1 for efficient therapy of AML [74].…”

Section: Tet1 Demethylation Associated Activation Of the Members In Tmentioning

confidence: 99%

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Cytosine Modifications and Distinct Functions of TET1 on Tumorigenesis

Ma¹,

Ji²,

Xie³

et al. 2020

Chromatin and Epigenetics

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Vast emerging evidences are linking the base modifications and gene expression involved in essential metabolic pathways. Among the base modification markers extensively studied, 5-methylcytosine (5mC) and its oxidative derivatives (5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC)) dynamically occur in DNA and RNA and have been acknowledged as the important epigenetic markers involved in regulation of cellular biological processes. The modification of C has been characterized biochemically, molecularly, and phenotypically, including elucidation of its methyltransferase complexes (writer), demethylases (eraser), 10-11 translocation proteins (TETs), and direct interaction proteins (readers). The levels and the landscapes of these epigenetic markers in the epitranscriptomes and epigenomes are precisely and dynamically regulated by the fine-tuned coordination of the writers and erasers in accordance with stages of the growth, development, and reproduction as naturally programmed during the life span. In mammalian genome, the TET family is consisted of three members, including TET1, TET2, and TET3. The link between aberrant modifications and diseases, such as cancers, neurodegenerative disorders, and heart diseases, has been appreciated. This review article will highlight the research advances in the writers and erasers for the modifications of cytosine in genome, as well as the dual function of TET1 in tumorigenesis as a tumor suppressor and a promoter. Additionally, the future research directions are addressed.

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“…In the United States, 19,940 new AML cases are expected to be diagnosed, and 11,180 AML-associated deaths are expected to occur in 2020 ( https://www.seer.cancer.gov/ ). While there have been countless efforts to develop novel therapeutic strategies suited to the treatment of AML, the majority of patients still suffer from poor outcomes, with recent reports estimating a 5-year survival rate of 40% among AML patients 1 , 2 . As such, there is a clear need to better understand the molecular basis for AML in order to expedite the development of more efficacious therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

miR-550-1 functions as a tumor suppressor in acute myeloid leukemia via the hippo signaling pathway

Hu¹,

Yu²,

Li³

et al. 2020

Int. J. Biol. Sci.

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MicroRNAs (miRNAs) and N 6 -methyladenosine (m 6 A) are known to serve as key regulators of acute myeloid leukemia (AML). Our previous microarray analysis indicated miR-550-1 was significantly downregulated in AML. The specific biological roles of miR-550-1 and its indirect interactions and regulation of m 6 A in AML, however, remain poorly understood. At the present study, we found that miR-550-1 was significantly down-regulated in primary AML samples from human patients, likely owing to hypermethylation of the associated CpG islands. When miR-550-1 expression was induced, it impaired AML cell proliferation both in vitro and in vivo , thus suppressing tumor development. When ectopically expressed, miR-550-1 drove the G0/1 cell cycle phase arrest, differentiation, and apoptotic death of affected cells. We confirmed mechanistically that WW-domain containing transcription regulator-1 ( WWTR1 ) gene was a downstream target of miR-550-1. Moreover, we also identified Wilms tumor 1-associated protein ( WTAP ), a vital component of the m 6 A methyltransferase complex, as a target of miR-550-1. These data indicated that miR-550-1 might mediate a decrease in m 6 A levels via targeting WTAP , which led to a further reduction in WWTR1 stability. Using gain- and loss-of-function approaches, we were able to determine that miR-550-1 disrupted the proliferation and tumorigenesis of AML cells at least in part via the direct targeting of WWTR1 . Taken together, our results provide direct evidence that miR-550-1 acts as a tumor suppressor in the context of AML pathogenesis, suggesting that efforts to bolster miR-550-1 expression in AML patients may thus be a viable clinical strategy to improve patient outcomes.

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Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia

Cited by 54 publications

References 66 publications

Tet Enzymes, Variants, and Differential Effects on Function

Tet Enzymes, Variants, and Differential Effects on Function

Cytosine Modifications and Distinct Functions of TET1 on Tumorigenesis

miR-550-1 functions as a tumor suppressor in acute myeloid leukemia via the hippo signaling pathway

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