A panel of epigenetically dysregulated Wnt signaling pathway genes for non-invasive diagnosis of pediatric acute lymphoblastic leukemia

2021 ◽  
pp. 1-12
Author(s):  
Syeda Saliha Hassan ◽  
Neha Maqsood ◽  
Qingbing Wang ◽  
Sun Tao ◽  
Saima Sadaf
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Lymphoblastic Leukemia ◽  
Wnt Signaling Pathway ◽  
P Value ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Promoter Dna Methylation ◽  
Promoter Dna

BACKGROUND: Genetic and epigenetic dysregulation of Wnt signaling pathway is widely linked up with abnormal proliferation and/or epithelial-to-mesenchymal transition, in different cancer cell types. OBJECTIVE: In the present research, we have tested whether promoter DNA methylation of a set of Wnt/non-Wnt genes such as [cadherin-2 (CDH2)], “present in circulation”, could serve as “bone-marrow biopsy surrogate” and help in diagnosing the status, sub-type or treatment outcome in pediatric acute lymphoblastic leukemia (ALL) patients. METHODS: Promoter DNA methylation was quantified in the bisulfite modified blood from the pediatric ALL patients (n= 86) in comparison with age-matched cancer-free subjects (n= 28), using real-time methylation specific PCR followed by rigorous statistical validations. RESULTS: The observed methylation index, sensitivity and specificity of selected molecular markers (viz., SALL1, WNT5α, LRP1b, CDH2) in patients’ liquid-biopsies was clinically significant showing high positive correlation in the pre-B ALL cases (p-value < 0.001). A substantial drop in promoter methylation signal of the follow-up/post-treatment patients was also noted (p-value < 0.001), which suggested an impending role of minimally invasive liquid-biopsy approach in the diagnosis and/or therapeutic monitoring of pediatric leukemia. CONCLUSIONS: Whilst the reported metadata provides useful insight into the plausible involvement of epigenetic glitches in leukemogensis, our findings strengthen the remarkable functional consequences of dysregulated Wnt signaling genes in the hematological malignancies besides offering a novel panel of epigenetic marks.

Different Activation of WNT Signaling Pathway in B-Cell and T-Cell Acute Leukemias.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4317-4317
Author(s):  
Muge Sayitoglu ◽  
Ozden Hatirnaz ◽  
Yucel Erbilgin ◽  
Fatmahan Atalar ◽  
Ugur Ozbek
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Wnt Signaling ◽  
B Cell ◽  
Signaling Pathway ◽  
Peripheral Blood ◽  
Lymphoblastic Leukemia ◽  
Wnt Signaling Pathway ◽  
Hematopoietic Cells ◽  
Expression Levels

Abstract WNT signaling pathway proteins function as hematopoietic growth factors and regulate proliferation in normal T-cell and B-cell development. Recent experimental evidence demonstrated that oncogenic transformation in leukemias of both lymphoid and myeloid lineages is dependent on WNT signaling. Not much is known about activation of WNT signaling pathway, its ligands and receptors in hematopoiesis and leukemia pathogenesis. To define its role in leukemia, we aimed to determine mRNA levels of the critical members of WNT pathway (WNT5A, WNT10B, FZ5, β catenin, APC, TCF-1 and LEF-1) by using quantitative real time PCR in acute lymphoblastic leukemia (ALL) patients (T-cell n=42, B-cell n=46 and pre B-cell n=30) and normal hematopoietic cells (bone marrow n=6, peripheral blood n=10, and CD19+ cells from peripheral blood). These genes expressed varying levels in B-cells, preB-cells and T-cells. In the B-cell leukemia patients, WNT5A was expressed notably (OR=58.05 CI 95% 1.63–1219.55, p&gt;0,001). WNT5A directs Ca++ dependent signaling by PKC and a G protein dependent manner which is an alternative pathway for beta-catenin mediated signaling. Also LEF-1 levels were higher in B-ALL patients and APC expression was down regulated when compared to normal tissue (OR=18.81 CI 95% 0.34–5703, p&gt;0.001 and OR=0.212 CI 95% 0.006–8.816, p=0.001, respectively). It is known that LEF-1 blocks APC mediated β catenin nuclear export and activates transcription of various transforming genes, including cyclin, D1, c-myc, MMP7, and LEF-1 itself. WNT5A or WNT10B proteins were not found to be up regulated in preB-ALL whereas APC and LEF-1 gene expressions were increased compared to normal hematopoietic cells (OR=32.97 CI 95% 0.27–1281, 38 p&gt;0.001 and OR=5.57 CI 95% 0.28–89.51, p=0.01, respectively). We found increased TCF-1 expression (7.4 fold) without any β catenin accumulation in T-ALL patients. It is known that TCF-1 in absence of β catenin functions as a tumor suppressor gene. WNT5A, APC and LEF-1 gene expression levels were also different between T-cell, B-cell and preB cell ALL cases. WNT5A expression had the highest levels in B-ALL compared to T-ALL cases, whereas the highest APC expression levels were observed in preB and T-ALL patients. Also LEF-1 expression levels were significantly different between preB and T-cell ALL patients. Taken together these results indicate that WNT signaling genes have abnormal expression and are active in acute lymphoblastic leukemia. This data suggests different WNT activation mechanisms exist in the leukemic transformation in different hematopoietic cells.

scholarly journals TET2 promoter DNA methylation and expression analysis in pediatric B-cell acute lymphoblastic leukemia

2014 ◽  
Vol 6 (1) ◽  
Author(s):  
Ewa Musialik ◽  
Mateusz Bujko ◽  
Agnieszka Wypych ◽  
Michał Matysiak ◽  
Janusz Aleksander Siedlecki
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Expression Analysis ◽  
Lymphoblastic Leukemia ◽  
Promoter Dna Methylation ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Promoter Dna

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

2017 ◽  
Vol 14 (4) ◽  
pp. 5034-5038
Author(s):  
Gholamreza Bahari ◽  
Mohammad Hashemi ◽  
Majid Naderi ◽  
Simin Sadeghi-Bojd ◽  
Mohsen Taheri
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
Expression Analysis ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Promoter Dna Methylation ◽  
Promoter Dna

Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3462-3469 ◽  
Author(s):  
José Román-Gómez ◽  
Lucia Cordeu ◽  
Xabier Agirre ◽  
Antonio Jiménez-Velasco ◽  
Edurne San José-Eneriz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Wnt Signaling Pathway ◽  
Disease Free Survival ◽  
Wnt Inhibitor ◽  
Wnt Inhibitors

Abstract Activation of the Wnt/β-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/β-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL cell lines and samples from patients with ALL. Methylation of Wnt inhibitors was associated with activation of the Wnt-signaling pathway as demonstrated by the up-regulation of the Wnt target genes WNT16, FZ3, TCF1, LEF1, and cyclin D1 in cell lines and samples and the nuclear localization of β-catenin in cell lines. Treatment of ALL cells with the Wnt inhibitor quercetin or with the demethylating agent 5-aza-2′-deoxycytidine induced an inactivation of the Wnt pathway and induced apoptosis of ALL cells. Finally, in a group of 261 patients with newly diagnosed ALL, abnormal methylation of Wnt inhibitors was associated with decreased 10-year disease-free survival (25% versus 66% respectively, P < .001) and overall survival (28% versus 61% respectively, P = .001). Our results indicate a role of abnormal Wnt signaling in ALL and establish a group of patients with a significantly worse prognosis (methylated group).

scholarly journals Methylation status of Wnt signaling pathway genes affects the clinical outcome of Philadelphia-positive acute lymphoblastic leukemia

2008 ◽  
Vol 99 (9) ◽  
pp. 1865-1868 ◽  
Author(s):  
Vanesa Martin ◽  
Xabier Agirre ◽  
Antonio Jiménez-Velasco ◽  
Edurne San José-Eneriz ◽  
Lucia Cordeu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Clinical Outcome ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Lymphoblastic Leukemia ◽  
Methylation Status ◽  
Wnt Signaling Pathway

scholarly journals Promoter DNA Methylation Pattern Identifies Prognostic Subgroups in Childhood T-Cell Acute Lymphoblastic Leukemia

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65373 ◽  
Author(s):  
Magnus Borssén ◽  
Lars Palmqvist ◽  
Kristina Karrman ◽  
Jonas Abrahamsson ◽  
Mikael Behrendtz ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Methylation Pattern ◽  
Promoter Dna Methylation ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Dna Methylation Pattern ◽  
Promoter Dna

scholarly journals DNA methylation mediated RSPO2 to promote follicular development in mammals

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xiaofeng Zhou ◽  
Yingting He ◽  
Nian Li ◽  
Guofeng Bai ◽  
Xiangchun Pan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Wnt Signaling Pathway ◽  
Follicular Development ◽  
Expression Level

AbstractIn female mammals, the proliferation, apoptosis, and estradiol-17β (E2) secretion of granulosa cells (GCs) have come to decide the fate of follicles. DNA methylation and RSPO2 gene of Wnt signaling pathway have been reported to involve in the survival of GCs and follicular development. However, the molecular mechanisms for how DNA methylation regulates the expression of RSPO2 and participates in the follicular development are not clear. In this study, we found that the mRNA and protein levels of RSPO2 significantly increased during follicular development, but the DNA methylation level of RSPO2 promoter decreased gradually. Inhibition of DNA methylation or DNMT1 knockdown could decrease the methylation level of CpG island (CGI) in RSPO2 promoter and upregulate the expression level of RSPO2 in porcine GCs. The hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of transcription factor E2F1 and promoted the transcriptional activity of RSPO2. Moreover, RSPO2 promoted the proliferation of GCs with increasing the expression level of PCNA, CDK1, and CCND1 and promoted the E2 secretion of GCs with increasing the expression level of CYP19A1 and HSD17B1 and inhibited the apoptosis of GCs with decreasing the expression level of Caspase3, cleaved Caspase3, cleaved Caspase8, cleaved Caspase9, cleaved PARP, and BAX. In addition, RSPO2 knockdown promoted the apoptosis of GCs, blocked the development of follicles, and delayed the onset of puberty with decreasing the expression level of Wnt signaling pathway-related genes (LGR4 and CTNNB1) in vivo. Taken together, the hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of E2F1 and enhanced the transcription of RSPO2, which further promoted the proliferation and E2 secretion of GCs, inhibited the apoptosis of GCs, and ultimately ameliorated the development of follicles through Wnt signaling pathway. This study will provide useful information for further exploration on DNA-methylation-mediated RSPO2 pathway during follicular development.

scholarly journals Clinical characteristics and outcomes of patients with pediatric acute lymphoblastic leukemia after induction of chemotherapy: a pilot descriptive correlational study from Palestine

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ramzi Shawahna ◽  
Sultan Mosleh ◽  
Yahya Odeh ◽  
Rami Halawa ◽  
Majd Al-Ghoul
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Blood Cells ◽  
Clinical Characteristics ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
P Value ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Objective Pediatric acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer among children. This study was conducted to describe and correlate the clinical characteristics and outcomes of treatment of patients with pediatric ALL in the main referral hospital in Palestine. Results Complete data of 69 patients were included in this analysis. The majority (79.7%) of the patients had B-ALL phenotype. After induction chemotherapy, remission was experienced by the vast majority of the patients and 5 (7.2%) experienced relapses. Cytogenetics for patients with B-ALL phenotype indicated that 10 (18.2%) patients had t(12, 21) translocation, 5 (9.1%) had hyperdiploidy, 4 (7.3%) had t(1, 19) translocation, and 2 (3.6%) had t(9, 22) translocation. The initial white blood cells (p value < 0.001), absolute neutrophils (p value = 0.011), and hemoglobin (p value < 0.001) were significantly lower in patients with B-cell ALL. Platelet counts were significantly lower (p value = 0.012) in patients with splenomegaly and those with bleeding symptoms (p value = 0.008). Presence of palmar pollar was positively associated (p value = 0.035) with T-cell ALL. Presence of hepatomegaly was positively associated (p value < 0.001) with splenomegaly.

scholarly journals DNA Methylation-Mediated Silencing of Mir-204 Enhances the Occurrence of T-Cell Acute Lymphoblastic Leukemia By Upregulating MMP-2 and MMP-9 through the NF-Κb Signaling Pathway

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Dabing Chen ◽  
Tingting Xiao ◽  
Dandan Lin ◽  
Haojie Zhu ◽  
Jingjing Xu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Matrix Metalloproteinase ◽  
Western Blot ◽  
Signaling Pathway ◽  
Promoter Region ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

Background : MicroRNAs (miR) are non-coding RNAs that play a role in regulation multiple functions in different cell types. Previous studies have shown that miR-204 is downregulated in T-ALL. We previously reported that matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) gene polymorphisms may be associated with the risk of T-cell acute lymphoblastic leukemia (T-ALL). The present study aims to decipher the role of miR-204 and MMP-2/MMP-9 in T-ALL occurrence to guide the diagnosis and treatment of T-ALL in the clinics. Methods: Expression of miR-204 was determined in the bone marrow and peripheral blood samples from 70 T-ALL patients and 70 healthy volunteers by real-time quantitative PCR (RT-qPCR). Bisulfite sequencing PCR (BSP) was used to detect the DNA methylation levels of the miR-204 promoter region in T-ALL patients and T-ALL cell lines.The effect of miR-204 on cell proliferation was evaluated with the cell counting kit-8 solution (CCK-8) assay and by Hoechst and PI double staining. The binding site of miR-204 on IRAK1 was predicted by the Primer Premier 5.0 and the defined binding sequences were used to construct luciferase-tag plasmids. The regulation of IRAK1 expression by miR-204 was evaluated by RT-qPCR and Western blot analysis. With the purpose to confirm the role of MMP-2 and MMP-9 in the occurrence of T-ALL, we investigated the effect of related proteins on T-ALL cells using Western blot. To determine that miR-204 affects the occurrence of T-ALL disease by regulating the NF-KB signaling pathway, RT-qPCR and Western Blot were used for verification. Results: DNA methylation directly affects the miR-204 expression in the promoter region when T-ALL developed. Moreover, overexpression of miR-204 inhibited the proliferation and enhanced the apoptosis of T-ALL cells. Notably, overexpression of miR-204 inhibited IRAK1, which in turn inhibited the proliferation and enhanced the apoptosis of T-ALL cells. Furthermore, IRAK1 enhanced the expression of MMP-2 and MMP-9 through phosphorylation of of p65 NF-κB, and miR-204 modulated MMP-2 and MMP-9 expression through the IRAK1/NF-κB signaling pathway. Conclusion s : Our results demonstrate that in T-ALL cells, DNA methylation-mediated silencing of miR-204 regulates the expression of MMP-2 and MMP-9 through increased transcription of IRAK1, and activation of the NF-κB signaling pathway. These data provide a potential mechanism for the role of MMP-2 and MMP-9 in the occurrence of T-ALL. Further studies will be needed to demonstrate whether demethylation of miR-204 may be a promising treatment for T-ALL. Disclosures No relevant conflicts of interest to declare.

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