Aberrant DNA methylation of <i>PTPRG</i> as one possible mechanism of its under‐expression in CML patients in the State of Qatar

Ismail, Mohamed A.; Samara, Muthanna; Sayab, Ali Al; Alsharshani, Mohamed; Yassin, Mohamed A; Varadharaj, Govindarajulu; Vezzalini, Marzia; Tomasello, Luisa; Monne, Maria; Morsi, Hisham; Qoronfleh, M. Walid; Zayed, Hatem; Cook, Richard T.; Sorio, Claudio; Modjtahedi, Helmout; Al‐Dewik, Nader

doi:10.1002/mgg3.1319

Cited by 7 publications

(12 citation statements)

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“…Another mechanism was recently found to occur in patients with osteosarcoma involving the long non-coding RNA PTPRG-AS1. Overexpression of PTPRG-AS1 may predict the poor prognosis of patients and may have a (Della Peruta et al, 2010;Vezzalini et al, 2017;Ismail et al, 2020;Ismail et al, 2021) Lung Adenocarcinoma Specific germline polymorphisms such as SNPs on PTPRG gene may influence the survival of patients with lung adenocarcinoma Galvan et al (2015) Frontiers in Cell and Developmental Biology | www.frontiersin.org promoting effect on osteosarcoma cell metastasis being associated to increased migratory abilities of Saos-2 cells (Ge et al, 2021).…”

Section: Sarcomamentioning

confidence: 99%

“…The reduced binding of CTCF with the intron 1 of PTPRG sequence could weaken the formation of chromatin regulatory structures essential for the expression of distant genes ( van Roon et al, 2011 ). Additionally, high levels of methylation have been found in chronic myeloid leukemia (CML) patients ( Ismail et al, 2020 ). Instead, PTPRG promoter methylation was regularly associated with decreased protein expression and has been reported in several malignancies.…”

Section: Mechanisms Promoting Ptprg Silencing In Cancermentioning

confidence: 99%

“…Furthermore, recent results have highlighted a high frequency of CpG island methylation in CML patients compared with control group. Interestingly, hypermethylation of CpG islands in PTPRG intron 1 was identified in a group of patients that failed the tyrosine kinase inhibitors (TKIs) response compared to a newly diagnosed one ( Ismail et al, 2020 ). In almost all studies performed on the methylation of PTPRG promoter, treatment with demethylating agents (including 5-azacytidine) restored the expression of PTPRG ( van Doorn et al, 2005 ; Cheung et al, 2008 ; Della Peruta et al, 2010 ; Shu et al, 2010 ; Stevenson et al, 2014 ; Xiao et al, 2014 ; Tomasello et al, 2020 ).…”

Section: Mechanisms Promoting Ptprg Silencing In Cancermentioning

confidence: 99%

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The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

Böni

Sorio

2022

Front. Cell Dev. Biol.

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Members of the Protein Tyrosine Phosphatase (PTPs) family are associated with growth regulation and cancer development. Acting as natural counterpart of tyrosine kinases (TKs), mainly involved in crucial signaling pathways such as regulation of cell cycle, proliferation, invasion and angiogenesis, they represent key parts of complex physiological homeostatic mechanisms. Protein tyrosine phosphatase gamma (PTPRG) is classified as a R5 of the receptor type (RPTPs) subfamily and is broadly expressed in various isoforms in different tissues. PTPRG is considered a tumor-suppressor gene (TSG) mapped on chromosome 3p14-21, a region frequently subject to loss of heterozygosity in various tumors. However, reported mechanisms of PTPRG downregulation include missense mutations, ncRNA gene regulation and epigenetic silencing by hypermethylation of CpG sites on promoter region causing loss of function of the gene product. Inactive forms or total loss of PTPRG protein have been described in sporadic and Lynch syndrome colorectal cancer, nasopharyngeal carcinoma, ovarian, breast, and lung cancers, gastric cancer or diseases affecting the hematopoietic compartment as Lymphoma and Leukemia. Noteworthy, in Central Nervous System (CNS) PTPRZ/PTPRG appears to be crucial in maintaining glioblastoma cell-related neuronal stemness, carving out a pathological functional role also in this tissue. In this review, we will summarize the current knowledge on the role of PTPRG in various human cancers.

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Section: Sarcomamentioning

confidence: 99%

Section: Mechanisms Promoting Ptprg Silencing In Cancermentioning

confidence: 99%

Section: Mechanisms Promoting Ptprg Silencing In Cancermentioning

confidence: 99%

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The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

Böni

Sorio

2022

Front. Cell Dev. Biol.

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“…Methylation play an extremely important role in the regulation of PTPRG expression in CML—a feature shared with other malignancies [ 119 ]. In CML, promoter and intron-1 sequences of the PTPRG gene are consistently hyper-methylated by DNMT1/DNMT3-b upregulation, due to increased β-catenin stability [ 118 , 120 ]. Many studies mentioned above have underlined how multiple processes involving PPs converge to stabilize and activate the WNT/β-catenin cascade becoming part of the CML BP progression and pathogenesis.…”

Section: Role Of Phosphatases In Chronic Myeloid Leukemiamentioning

confidence: 99%

Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia

Böni

Sorio

2021

Cancers

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Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by BCR-ABL1 oncogene expression. This dysregulated protein-tyrosine kinase (PTK) is known as the principal driver of the disease and is targeted by tyrosine kinase inhibitors (TKIs). Extensive documentation has elucidated how the transformation of malignant cells is characterized by multiple genetic/epigenetic changes leading to the loss of tumor-suppressor genes function or proto-oncogenes expression. The impairment of adequate levels of substrates phosphorylation, thus affecting the balance PTKs and protein phosphatases (PPs), represents a well-established cellular mechanism to escape from self-limiting signals. In this review, we focus our attention on the characterization of and interactions between PTKs and PPs, emphasizing their biological roles in disease expansion, the regulation of LSCs and TKI resistance. We decided to separate those PPs that have been validated in primary cell models or leukemia mouse models from those whose studies have been performed only in cell lines (and, thus, require validation), as there may be differences in the manner that the associated pathways are modified under these two conditions. This review summarizes the roles of diverse PPs, with hope that better knowledge of the interplay among phosphatases and kinases will eventually result in a better understanding of this disease and contribute to its eradication.

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“…Epigenetic events, such as the hyper-methylation of its promoter region as well as intron 1, negatively regulate the transcription of PTPRG, as demonstrated in CML and childhood acute lymphoblastic leukemia [ 16 , 18 , 19 , 20 ]. Re-expression of this protein occurs in leukocytes (especially neutrophils) of CML patients following targeted therapy [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Landscape of Chronic Myeloid Leukemia K562 Cells Overexpressing the Tumor Suppressor Gene PTPRG

Lombardi

Latorre

Mosca

et al. 2022

IJMS

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This study concerns the analysis of the modulation of Chronic Myeloid Leukemia (CML) cell model K562 transcriptome following transfection with the tumor suppressor gene encoding for Protein Tyrosine Phosphatase Receptor Type G (PTPRG) and treatment with the tyrosine kinase inhibitor (TKI) Imatinib. Specifically, we aimed at identifying genes whose level of expression is altered by PTPRG modulation and Imatinib concentration. Statistical tests as differential expression analysis (DEA) supported by gene set enrichment analysis (GSEA) and modern methods of ontological term analysis are presented along with some results of current interest for forthcoming experimental research in the field of the transcriptomic landscape of CML. In particular, we present two methods that differ in the order of the analysis steps. After a gene selection based on fold-change value thresholding, we applied statistical tests to select differentially expressed genes. Therefore, we applied two different methods on the set of differentially expressed genes. With the first method (Method 1), we implemented GSEA, followed by the identification of transcription factors. With the second method (Method 2), we first selected the transcription factors from the set of differentially expressed genes and implemented GSEA on this set. Method 1 is a standard method commonly used in this type of analysis, while Method 2 is unconventional and is motivated by the intention to identify transcription factors more specifically involved in biological processes relevant to the CML condition. Both methods have been equipped in ontological knowledge mining and word cloud analysis, as elements of novelty in our analytical procedure. Data analysis identified RARG and CD36 as a potential PTPRG up-regulated genes, suggesting a possible induction of cell differentiation toward an erithromyeloid phenotype. The prediction was confirmed at the mRNA and protein level, further validating the approach and identifying a new molecular mechanism of tumor suppression governed by PTPRG in a CML context.

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Aberrant DNA methylation of PTPRG as one possible mechanism of its under‐expression in CML patients in the State of Qatar

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 47 publications

The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia

Gene Expression Landscape of Chronic Myeloid Leukemia K562 Cells Overexpressing the Tumor Suppressor Gene PTPRG

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