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Journal ArticleDOI

Immunotherapeutic Potential of m6A-Modifiers and MicroRNAs in Controlling Acute Myeloid Leukaemia.

18 Jun 2021-Biomedicines (Multidisciplinary Digital Publishing Institute)-Vol. 9, Iss: 6, pp 690
TL;DR: In this article, the therapeutic potential of m6A-modifiers in controlling haematological disorders, especially acute myeloid leukaemia (AML), was summarized.
Abstract: Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies have been predominantly focused on DNA methylation, histone modifications, and chromatin remodelling. Epitranscriptomics is an emerging field that encompasses the study of RNA modifications that do not affect the RNA sequence but affect functionality via a series of RNA binding proteins called writer, reader and eraser. Several kinds of epi-RNA modifications are known, such as 6-methyladenosine (m6A), 5-methylcytidine (m5C), and 1-methyladenosine. M6A modification is the most studied and has large therapeutic implications. In this review, we have summarised the therapeutic potential of m6A-modifiers in controlling haematological disorders, especially acute myeloid leukaemia (AML). AML is a type of blood cancer affecting specific subsets of blood-forming hematopoietic stem/progenitor cells (HSPCs), which proliferate rapidly and acquire self-renewal capacities with impaired terminal cell-differentiation and apoptosis leading to abnormal accumulation of white blood cells, and thus, an alternative therapeutic approach is required urgently. Here, we have described how RNA m6A-modification machineries EEE (Editor/writer: Mettl3, Mettl14; Eraser/remover: FTO, ALKBH5, and Effector/reader: YTHDF-1/2) could be reformed into potential druggable candidates or as RNA-modifying drugs (RMD) to treat leukaemia. Moreover, we have shed light on the role of microRNAs and suppressors of cytokine signalling (SOCS/CISH) in increasing anti-tumour immunity towards leukaemia. We anticipate, our investigation will provide fundamental knowledge in nurturing the potential of RNA modifiers in discovering novel therapeutics or immunotherapeutic procedures.
Citations
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Journal ArticleDOI
TL;DR: Zhang et al. as discussed by the authors systematically summarized the latest research progress on METTL14 as a new biomarker for cancer diagnosis and its biological function in human tumors and discuss its potential clinical application.
Abstract: RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N6-methyladenine (m6A) is the most abundant RNA modification. Methyltransferase-like 14 (METTL14) is the central component of the m6A methylated transferase complex, which is involved in the dynamic reversible process of m6A modification. METTL14 acts as both an oncogene and tumor suppressor gene to regulate the occurrence and development of various cancers. The abnormal m6A level induced by METTL14 is related to tumorigenesis, proliferation, metastasis, and invasion. To date, the molecular mechanism of METTL14 in various malignant tumors has not been fully studied. In this paper, we systematically summarize the latest research progress on METTL14 as a new biomarker for cancer diagnosis and its biological function in human tumors and discuss its potential clinical application. This study aims to provide new ideas for targeted therapy and improved prognoses in cancer.

18 citations

Journal ArticleDOI
30 Sep 2021-Cancers
TL;DR: In this paper, a review of the possible biological mechanisms involved in the development of inflamm-aging, focusing on immune system alteration, oxidative stress, cellular senescence, and therapeutic strategies is presented.
Abstract: Anti-cancer treatments improve survival in children with cancer. A total of 80% of children treated for childhood cancer achieve 5-year survival, becoming long-term survivors. However, they undergo several chronic late effects related to treatments. In childhood cancer survivors a chronic low-grade inflammation, known as inflamm-aging, is responsible for frailty, a condition characterized by vital organ failure and by premature aging processes. Inflamm-aging is closely related to chemotherapy and radiotherapy, which induce inflammation, accumulation of senescent cells, DNA mutations, and the production of reactive oxygen species. All these conditions are responsible for the onset of secondary diseases, such as osteoporosis, cardiovascular diseases, obesity, and infertility. Considering that the pathobiology of frailty among childhood cancer survivors is still unknown, investigations are needed to better understand frailty’s biological and molecular processes and to identify inflamm-aging key biomarkers in order to facilitate the screening of comorbidities and to clarify whether treatments, normally used to modulate inflamm-aging, may be beneficial. This review offers an overview of the possible biological mechanisms involved in the development of inflamm-aging, focusing our attention on immune system alteration, oxidative stress, cellular senescence, and therapeutic strategies.

14 citations

Journal ArticleDOI
30 Apr 2022-Cells
TL;DR:
Abstract: Simple Summary Hepatoblastoma is the most common malignant pediatric tumor of the liver. Unlike hepatocellular carcinoma (HCC) which has been associated with hepatitis B virus infection or cirrhosis, the etiology of hepatoblastoma remains vague. Genetic syndromes, including familial adenomatous polyposis (FAP), Beckwith-Wiedemann syndrome (BWS), and trisomy 18 syndrome, have been associated with hepatoblastoma. BWS is an overgrowth syndrome which exhibits an alteration of genomic imprinting on chromosome 11p15.5. N6-Methyladenosine (M6A) is an RNA modification with rampant involvement in the metabolism of cells and malignant diseases. It has been observed to impact the development of various cancers via its governance of gene expression. Here, we explore the role of m6A and its genetic associates in promoting HB, and the impact this may have on our future management of the disease. Abstract Hepatoblastoma (HB) is a rare primary malignancy of the developing fetal liver. Its course is profoundly influenced by genetics, in the context of sporadic mutation or genetic syndromes. Conventionally, subtypes of HB are histologically determined based on the tissue type that is recapitulated by the tumor and the direction of its differentiation. This classification is being reevaluated based on advances on molecular pathology. The therapeutic approach comprises surgical intervention, chemotherapy (in a neoadjuvant or post-operative capacity), and in some cases, liver transplantation. Although diagnostic modalities and treatment options are evolving, some patients experience complications, including relapse, metastatic spread, and suboptimal response to chemotherapy. As yet, there is no consistent framework with which such outcomes can be predicted. N6-methyladenosine (m6A) is an RNA modification with rampant involvement in the normal processing of cell metabolism and neoplasia. It has been observed to impact the development of a variety of cancers via its governance of gene expression. M6A-associated genes appear prominently in HB. Literature data seem to underscore the role of m6A in promotion and clinical course of HB. Illuminating the pathogenetic mechanisms that drive HB are promising additions to the understanding of the clinically aggressive tumor behavior, given its potential to predict disease course and response to therapy. Implicated genes may also act as targets to facilitate the evolving personalized cancer therapy. Here, we explore the role of m6A and its genetic associates in the promotion of HB, and the impact this may have on the management of this neoplastic disease.

7 citations

Journal ArticleDOI
30 Aug 2021-Cells
TL;DR: In this article, the authors proposed to improve the efficacy of ICB-therapy by co-targeting molecular checkpoints especially N6A-modification machineries which can be reformed into RNA modifying drugs (RMD).
Abstract: Cellular immunotherapy has recently emerged as a fourth pillar in cancer treatment co-joining surgery, chemotherapy and radiotherapy. Where, the discovery of immune checkpoint blockage or inhibition (ICB/ICI), anti-PD-1/PD-L1 and anti-CTLA4-based, therapy has revolutionized the class of cancer treatment at a different level. However, some cancer patients escape this immune surveillance mechanism and become resistant to ICB-therapy. Therefore, a more advanced or an alternative treatment is required urgently. Despite the functional importance of epitranscriptomics in diverse clinico-biological practices, its role in improving the efficacy of ICB therapeutics has been limited. Consequently, our study encapsulates the evidence, as a possible strategy, to improve the efficacy of ICB-therapy by co-targeting molecular checkpoints especially N6A-modification machineries which can be reformed into RNA modifying drugs (RMD). Here, we have explained the mechanism of individual RNA-modifiers (editor/writer, eraser/remover, and effector/reader) in overcoming the issues associated with high-dose antibody toxicities and drug-resistance. Moreover, we have shed light on the importance of suppressor of cytokine signaling (SOCS/CISH) and microRNAs in improving the efficacy of ICB-therapy, with brief insight on the current monoclonal antibodies undergoing clinical trials or already approved against several solid tumor and metastatic cancers. We anticipate our investigation will encourage researchers and clinicians to further strengthen the efficacy of ICB-therapeutics by considering the importance of epitranscriptomics as a personalized medicine.

6 citations

Journal ArticleDOI
TL;DR: It is hypothesized that m6A modification could dysregulate the expression of glucose, lipid, amino acid metabolism, and other metabolites or building blocks of cells by adaptation to the hypoxic tumor microenvironment, an increase in glycolysis, mitochondrial dysfunction, and abnormal expression of metabolic enzymes, metabolic receptors, transcription factors as well as oncogenic signaling pathways in both hematological malignancies and solid tumors.
Abstract: Methylation of adenosine in RNA to N6-methyladenosine (m6A) is widespread in eukaryotic cells with his integral RNA regulation. This dynamic process is regulated by methylases (editors/writers), demethylases (remover/erasers), and proteins that recognize methylation (effectors/readers). It is now evident that m6A is involved in the proliferation and metastasis of cancer cells, for instance, altering cancer cell metabolism. Thus, determining how m6A dysregulates metabolic pathways could provide potential targets for cancer therapy or early diagnosis. This review focuses on the link between the m6A modification and the reprogramming of metabolism in cancer. We hypothesize that m6A modification could dysregulate the expression of glucose, lipid, amino acid metabolism, and other metabolites or building blocks of cells by adaptation to the hypoxic tumor microenvironment, an increase in glycolysis, mitochondrial dysfunction, and abnormal expression of metabolic enzymes, metabolic receptors, transcription factors as well as oncogenic signaling pathways in both hematological malignancies and solid tumors. These metabolism abnormalities caused by m6A’s modification may affect the metabolic reprogramming of cancer cells and then increase cell proliferation, tumor initiation, and metastasis. We conclude that focusing on m6A could provide new directions in searching for novel therapeutic and diagnostic targets for the early detection and treatment of many cancers.

5 citations

References
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Journal ArticleDOI
TL;DR: This work presents Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer, and uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions.
Abstract: We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.

13,008 citations

Journal ArticleDOI
15 May 2009-Science
TL;DR: It is shown here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro.
Abstract: DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference–mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.

5,155 citations

Journal ArticleDOI
Timothy J. Ley1, Christopher A. Miller1, Li Ding1, Benjamin J. Raphael2, Andrew J. Mungall3, Gordon Robertson3, Katherine A. Hoadley4, Timothy J. Triche5, Peter W. Laird5, Jack Baty1, Lucinda Fulton1, Robert S. Fulton1, Sharon Heath1, Joelle Kalicki-Veizer1, Cyriac Kandoth1, Jeffery M. Klco1, Daniel C. Koboldt1, Krishna L. Kanchi1, Shashikant Kulkarni1, Tamara Lamprecht1, David E. Larson1, G. Lin1, Charles Lu1, Michael D. McLellan1, Joshua F. McMichael1, Jacqueline E. Payton1, Heather Schmidt1, David H. Spencer1, Michael H. Tomasson1, John W. Wallis1, Lukas D. Wartman1, Mark A. Watson1, John S. Welch1, Michael C. Wendl1, Adrian Ally3, Miruna Balasundaram3, Inanc Birol3, Yaron S.N. Butterfield3, Readman Chiu3, Andy Chu3, Eric Chuah3, Hye Jung E. Chun3, Richard Corbett3, Noreen Dhalla3, Ranabir Guin3, An He3, Carrie Hirst3, Martin Hirst3, Robert A. Holt3, Steven J.M. Jones3, Aly Karsan3, Darlene Lee3, Haiyan I. Li3, Marco A. Marra3, Michael Mayo3, Richard A. Moore3, Karen Mungall3, Jeremy Parker3, Erin Pleasance3, Patrick Plettner3, Jacquie Schein3, Dominik Stoll3, Lucas Swanson3, Angela Tam3, Nina Thiessen3, Richard Varhol3, Natasja Wye3, Yongjun Zhao3, Stacey Gabriel6, Gad Getz6, Carrie Sougnez6, Lihua Zou6, Mark D.M. Leiserson2, Fabio Vandin2, Hsin-Ta Wu2, Frederick Applebaum7, Stephen B. Baylin8, Rehan Akbani9, Bradley M. Broom9, Ken Chen9, Thomas C. Motter9, Khanh Thi-Thuy Nguyen9, John N. Weinstein9, Nianziang Zhang9, Martin L. Ferguson, Christopher Adams10, Aaron D. Black10, Jay Bowen10, Julie M. Gastier-Foster10, Thomas Grossman10, Tara M. Lichtenberg10, Lisa Wise10, Tanja Davidsen11, John A. Demchok11, Kenna R. Mills Shaw11, Margi Sheth11, Heidi J. Sofia, Liming Yang11, James R. Downing, Greg Eley, Shelley Alonso12, Brenda Ayala12, Julien Baboud12, Mark Backus12, Sean P. Barletta12, Dominique L. Berton12, Anna L. Chu12, Stanley Girshik12, Mark A. Jensen12, Ari B. Kahn12, Prachi Kothiyal12, Matthew C. Nicholls12, Todd Pihl12, David Pot12, Rohini Raman12, Rashmi N. Sanbhadti12, Eric E. Snyder12, Deepak Srinivasan12, Jessica Walton12, Yunhu Wan12, Zhining Wang12, Jean Pierre J. Issa13, Michelle M. Le Beau14, Martin Carroll15, Hagop M. Kantarjian, Steven M. Kornblau, Moiz S. Bootwalla5, Phillip H. Lai5, Hui Shen5, David Van Den Berg5, Daniel J. Weisenberger5, Daniel C. Link1, Matthew J. Walter1, Bradley A. Ozenberger11, Elaine R. Mardis1, Peter Westervelt1, Timothy A. Graubert1, John F. DiPersio1, Richard K. Wilson1 
TL;DR: It is found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients and the databases from this study are widely available to serve as a foundation for further investigations of AMl pathogenesis, classification, and risk stratification.
Abstract: BACKGROUND—Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined The relationships between patterns of mutations and epigenetic phenotypes are not yet clear METHODS—We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis RESULTS—AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes Of these, an average of 5 are in genes that are recurrently mutated in AML A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcriptionfactor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumorsuppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%) Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories CONCLUSIONS—We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification (Funded by the National Institutes of Health) The molecular pathogenesis of acute myeloid leukemia (AML) has been studied with the use of cytogenetic analysis for more than three decades Recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, suggesting that acquired genetic abnormalities (ie, somatic mutations) have an essential role in pathogenesis 1,2 However, nearly 50% of AML samples have a normal karyotype, and many of these genomes lack structural abnormalities, even when assessed with high-density comparative genomic hybridization or single-nucleotide polymorphism (SNP) arrays 3-5 (see Glossary) Targeted sequencing has identified recurrent mutations in FLT3, NPM1, KIT, CEBPA, and TET2 6-8 Massively parallel sequencing enabled the discovery of recurrent mutations in DNMT3A 9,10 and IDH1 11 Recent studies have shown that many patients with

3,980 citations

Journal ArticleDOI
10 May 2012-Nature
TL;DR: The findings suggest that RNA decoration by m6A has a fundamental role in regulation of gene expression, and a subset of stimulus-dependent, dynamically modulated sites is identified.
Abstract: An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.

3,237 citations

Journal ArticleDOI
22 Jun 2012-Cell
TL;DR: A method is presented for transcriptome-wide m(6)A localization, which combines m( 6)A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq) and reveals insights into the epigenetic regulation of the mammalian transcriptome.

2,839 citations