Changes in the Expression of DNMTs Before and After Treatment with Methotrexate (MTX)/Mercaptopurine (6-MP) in B-Cell ALL Children

Mahmoud Imanei-Avaz; Azam Sadat Hashemi; Nasrin Ghasemi; Seyed Hossein  Hekmati Moghaddam; Fatemeh Pourrajab; Kazem Barzegar; Mahmood Vakili

doi:10.18502/ijpho.v14i2.15267

Mahmoud Imanei-Avaz International Campus of Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Azam Sadat Hashemi Hematology & Oncology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Nasrin Ghasemi Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Seyed Hossein Hekmati Moghaddam Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Fatemeh Pourrajab Department of Laboratory Sciences, School of Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Kazem Barzegar English Language Department, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Mahmood Vakili MD, MPH, Associate Professor in Community Medicine, Health Monitoring Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

DOI: https://doi.org/10.18502/ijpho.v14i2.15267

Keywords: DNA Methyltransferases (DNMTs), Methotrexate (MTX), Mercaptopurine (6-MP)

Abstract

Background: DNA methylation is catalyzed by DNA methyltransferases (DNMTs) which are encoded by DNMT1, DNMT3A, and DNMT3B. DNMTs play a major role in the abnormal methylation of tumor suppressors and cancer-related genes. Herein, this study explored the expression profile of DNMTs in pediatric patients with B-cell acute lymphoblastic leukemia (ALL), before and after methotrexate (MTX)/mercaptopurine (6-MP) treatment.

Materials and Methods: This before-after prospective study included 30 matched children in sex and age (20 children with B-cell ALL and 10 healthy children used as a control or calibrator group). The expression profile of DNMTs was assessed at two-time points; at the diagnosis time and after MTX/6-MP treatment in the consolidation-maintenance phase of therapy. Notable, all pediatric patients included in this study continued the therapy without adverse events, except two children who were excluded from the study.

Results: The average age of the patient group was 7.1 ± 1.3 years (in the range of 4-9 years), and the average age of the control group was 8.3 ± 1.7 years (6-10 years). The expression profile of DNMTs in B-cell ALL children was obtained completely different from that in the healthy group. After MTX/6-MP treatment of B-cell ALL children, the expression levels of DNMT1 and 3A were increased (p <0.01 & 0.04, respectively), and the expression level of DNMT3B was decreased (p <0.01), significantly.

Conclusions: In ALL, the expression profile of DNMTs would be changed whereby contribute to abnormal growth and maturation capacity of leukemic stem cells and MTX/6-MP treatment could reverse this profile from a cancerous phenotype to the normal one.