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Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications

Authors Lamim Lovatel V, de Souza Fernandez C, Ferreira Rodrigues E, de Cassia Tavares R, Sobral da Costa E, Abdelhay E, Coelho Soares Lima S, de Souza Fernandez T

Received 11 June 2019

Accepted for publication 18 November 2019

Published 23 January 2020 Volume 2020:12 Pages 543—556

DOI https://doi.org/10.2147/CMAR.S219026

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 5

Editor who approved publication: Dr Antonella D'Anneo


Viviane Lamim Lovatel,1 Cecilia de Souza Fernandez,2 Eliane Ferreira Rodrigues,1 Rita de Cassia Tavares,3 Elaine Sobral da Costa,4 Eliana Abdelhay,5 Sheila Coelho Soares Lima,6 Teresa de Souza Fernandez1

1Cytogenetics Department, Bone Marrow Transplantation Center (CEMO), National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil; 2Mathematical and Statistical Institute, Federal Fluminense University (UFF), Niterói, RJ, Brazil; 3Outpatient Department, Bone Marrow Transplantation Center (CEMO), National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil; 4Pediatrics Department, Faculty of Medicine, Federal Rio de Janeiro University (UFRJ), Rio de Janeiro, RJ, Brazil; 5Stem Cell Department, Bone Marrow Transplantation Center (CEMO), National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil; 6Molecular Carcinogenesis Program, National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil

Correspondence: Teresa de Souza Fernandez
Instituto Nacional de Câncer (INCA), Centro de Transplante de Medula Óssea, Laboratório de Citogenética, Praça Cruz Vermelha N o 23, 6º Andar. Centro, Rio de Janeiro, RJ CEP: 20230-130, Brasil
Tel +55 21 3207-1701
Email teresafernandez@inca.gov.br

Purpose: The aim of this study was to analyse the expression profiles of DNMT1, DNMT3A, DNMT3B (components of DNA methylation machinery), TET2 and APOBEC3B (components of DNA demethylation machinery) in pediatric MDS patients and investigate their associations with MDS subtypes, cytogenetics, evolution to acute myeloid leukemia (AML) and p15INK4B methylation level.
Patients and Methods: The expressions of DNMT1, DNMT3A, DNMT3B, TET2, and APOBEC3B were evaluated in 39 pediatric MDS patients by real-time quantitative PCR (qPCR). The quantification of p15INK4B methylation levels (MtL) was performed in 20 pediatric MDS patients by pyrosequencing. Mann–Whitney test was used to evaluate possible differences between the expression levels of selected in patients and donors, according to MDS subtypes, karyotypes, evolution to AML and p15INK4B MtL. The correlations between the expression levels of the different genes were assessed by Spearman rank correlation coefficient.
Results: We found that DNMTs expression levels were higher in pediatric MDS compared to donors [DNMT1 (p< 0.03), DNMT3A (p< 0.03), DNMT3B (p< 0.02)]. TET2 and APOBEC3B expression levels did not show a statistically significant difference between pediatric patients and donors. Considering MDS subtypes, patients at initial stage presented DNMT1 overexpression (p< 0.01), while DNMT3A (p< 0.02) and DNMT3B (p< 0.007) were overexpressed in advanced subtypes. TET2 and APOBEC3B expression did not differ in MDS subtypes. DNMT1 (p< 0.03), DNMT3B (p< 0.03), and APOBEC3B (p< 0.04) expression was higher in patients with normal karyotypes, while patients with abnormal karyotypes showed higher DNMT3A expression (p< 0.03). Karyotypes had no association with TET2 expression. DNMTs overexpression was observed in patients who showed disease evolution. A positive correlation was found between DNMTs expression and between APOBEC3B and DNMT3A/DNMT3B. However, TET2 expression was not correlated with DNMTs or APOBEC3B. p15INK4B MtL was higher in pediatric MDS patients compared with donors (p< 0.03) and its hypermethylation was associated with increased DNMT1 expression (p< 0.009).
Conclusion: Our results suggest that the overexpression of DNMTs and an imbalance between the expressions of the DNA methylation/demethylation machinery components play an important role in MDS development and evolution to AML. These results have clinical implications indicating the importance of DNMTs inhibitors for preventing or delaying the progression to leukemia in pediatric MDS patients.

Keywords: pediatric myelodysplastic syndrome, DNMTs, TET2, APOBEC3B

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