FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

Bahari, Gholamreza; Hashemi, Mohammad; Naderi, Majid; Sadeghi‐Bojd, Simin; Taheri, Mohsen

doi:10.3892/ol.2017.6796

Cited by 10 publications

(9 citation statements)

References 37 publications

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“…Acute lymphoblastic leukemia patients showed significantly lower TET2 mRNA levels compared to the controls. Our results are consistent with previous reports …”

Section: Discussionsupporting

confidence: 94%

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Low expression of TET2 gene in pediatric acute lymphoblastic leukemia is associated with poor clinical outcome

Zhang

Weng

Chen

et al. 2019

Int J Lab Hematology

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Introduction TET2, a member of the Ten‐Eleven translocation gene family, catalyzes the conversion of 5‐methylcytosine to 5‐hydroxymethylcytosine in DNA. Low expression of TET2 has been reported as a prognostic factor for several types of malignancies in adult patients. However, there have been few data on the effect of TET2 mRNA level on the prognosis of children with ALL so far. Methods In this study, TET2 expression of samples cryopreserved in the liquid nitrogen from January 1, 2007 through December 31, 2011 was retrospectively analyzed in 136 newly diagnosed ALL patients by real‐time polymerase chain reaction (PCR) assay. The patients' samples were divided into two groups by the median value of patients group and divided into TET2 low and TET2 high groups. Results A total of 136 childhood ALL patients demonstrated lower TET2 expression than control group (P = .038). TET2 mRNA expression levels were correlated with the disease status. In addition, patients with low TET2 expression had lower platelet counts and lower CR rates. Survival analysis showed that low TET2 expression in children with ALL was associated with lower 5‐year overall survival (OS) (63% vs 88%, P = .011) and event‐free survival (EFS) (60% vs 85%, P = .003). Multivariate analysis revealed that low TET2 expression was an independent poor prognostic factor of OS and EFS. Conclusion Low expression of TET2 in children with ALL is associated with poor prognosis and can be used as a molecular prognostic marker for risk group stratification.

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“…Acute lymphoblastic leukemia patients showed significantly lower TET2 mRNA levels compared to the controls. Our results are consistent with previous reports …”

Section: Discussionsupporting

confidence: 94%

“…Our results are consistent with previous reports. 17,18 Pan et al reported that TET2 deletion (knockout/mutation) led to hypermutagenicity, such as mutations in APC, FLT3, NF1, CBL, KMT2D, and NOTCH1 in hematopoietic stem/progenitor cells. 19 Mouly E group observed the development of B-cell tumor in TET2-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Low expression of TET2 gene in pediatric acute lymphoblastic leukemia is associated with poor clinical outcome

Zhang

Weng

Chen

et al. 2019

Int J Lab Hematology

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“…In addition, several studies have reported aberrant methylation of TSGs TET2 and CYP1B1 in ALL. Indeed, hypermethylation of TET2 51 and CYP1B1 52 as well as their decreased expression levels were detected in childhood ALL patients compared with healthy children and associated with worse overall survival. In the same context, the TSG DDIT3 was found to be hypermethylated in 66% of chronic myeloid leukemia cases.…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms

et al. 2019

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The epigenetic silencing of tumor suppressor genes (TSGs) is a common finding in several solid and hematological tumors involving various epigenetic readers and writers leading to enhanced cell proliferation and defective apoptosis. Thymoquinone (TQ), the major biologically active compound of black seed oil, has demonstrated anticancer activities in various tumors by targeting several pathways. However, its effects on the epigenetic code of cancer cells are largely unknown. In the present study, we performed RNA sequencing to investigate the anticancer mechanisms of TQ-treated T-cell acute lymphoblastic leukemia cell line (Jurkat cells) and examined gene expression using different tools. We found that many key epigenetic players, including ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 ( UHRF1), DNMT1,3A,3B, G9A, HDAC1,4,9, KDM1B , and KMT2A,B,C,D,E , were downregulated in TQ-treated Jurkat cells. Interestingly, several TSGs, such as DLC1, PPARG, ST7, FOXO6, TET2, CYP1B1, SALL4 , and DDIT3 , known to be epigenetically silenced in various tumors, including acute leukemia, were upregulated, along with the upregulation of several downstream pro-apoptotic genes, such as RASL11B, RASD1, GNG3, BAD , and BIK . Data obtained from RNA sequencing were confirmed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) in Jurkat cells, as well as in a human breast cancer cell line (MDA-MB-468 cells). We found that the decrease in cell proliferation and in the expression of UHRF1, DNMT1, G9a , and HDAC1 genes in both cancer cell (Jurkat cells and MDA-MB-468 cells) lines depends on the TQ dose. Our results indicate that the use of TQ as an epigenetic drug represents a promising strategy for epigenetic therapy for both solid and blood tumors by targeting both DNA methylation and histone post-translational modifications.

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“…TET1 and TET2 have overlapping functions [97], a level of redundancy that reflects their biological importance, whilst TET3 is thought to be important during reprogramming within the oocyte [98] although it has recently been shown to be important at later developmental stages within the retina [99]. The TET enzymes can be regulated at multiple levels, including through DNA methylation at the TET1 and TET2 promoters [100, 101], through the action of transcription factors such as HIF1β [102], and through regulation at the mRNA and protein level [103-107]. The TET enzymes are therefore highly responsive to environmental stimuli, which perhaps plays a role in their dynamic developmental role.…”

Section: Epigenetic Modificationsmentioning

confidence: 99%

Preterm Birth and the Risk of Neurodevelopmental Disorders - Is There a Role for Epigenetic Dysregulation?

Fitzgerald

Boardman

Drake

2018

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Preterm Birth (PTB) accounts for approximately 11% of all births worldwide each year and is a profound physiological stressor in early life. The burden of neuropsychiatric and developmental impairment is high, with severity and prevalence correlated with gestational age at delivery. PTB is a major risk factor for the development of cerebral palsy, lower educational attainment and deficits in cognitive functioning, and individuals born preterm have higher rates of schizophrenia, autistic spectrum disorder and attention deficit/hyperactivity disorder. Factors such as gestational age at birth, systemic inflammation, respiratory morbidity, sub-optimal nutrition, and genetic vulnerability are associated with poor outcome after preterm birth, but the mechanisms linking these factors to adverse long term outcome are poorly understood. One potential mechanism linking PTB with neurodevelopmental effects is changes in the epigenome. Epigenetic processes can be defined as those leading to altered gene expression in the absence of a change in the underlying DNA sequence and include DNA methylation/hydroxymethylation and histone modifications. Such epigenetic modifications may be susceptible to environmental stimuli, and changes may persist long after the stimulus has ceased, providing a mechanism to explain the long-term consequences of acute exposures in early life. Many factors such as inflammation, fluctuating oxygenation and excitotoxicity which are known factors in PTB related brain injury, have also been implicated in epigenetic dysfunction. In this review, we will discuss the potential role of epigenetic dysregulation in mediating the effects of PTB on neurodevelopmental outcome, with specific emphasis on DNA methylation and the α-ketoglutarate dependent dioxygenase family of enzymes.

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FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

Cited by 10 publications

References 37 publications

Low expression of TET2 gene in pediatric acute lymphoblastic leukemia is associated with poor clinical outcome

Low expression of TET2 gene in pediatric acute lymphoblastic leukemia is associated with poor clinical outcome

Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms

Preterm Birth and the Risk of Neurodevelopmental Disorders - Is There a Role for Epigenetic Dysregulation?

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