The urinary excretion of epigenetically modified DNA as a marker of pediatric ALL status and chemotherapy response.

The active DNA demethylation process may be linked to aberrant methylation and may be involved in leukemogenesis. We investigated the role of epigenetic DNA modifications in childhood acute lymphoblastic leukemia (ALL) diagnostics and therapy monitoring. We analyzed the levels of 5-methyl-2'-deoxycytidine (5-mdC) oxidation products in the cellular DNA and urine of children with ALL (at diagnosis and during chemotherapy, n = 55) using two-dimensional ultra-performance liquid chromatography with tandem mass spectrometry (2D UPLC-MS/MS). Moreover, the expression of Ten Eleven Translocation enzymes (TETs) at the mRNA and protein levels was determined. Additionally, the ascorbate level in the blood plasma was analyzed. Before treatment, the ALL patients had profoundly higher levels of the analyzed modified DNA in their urine than the controls. After chemotherapy, we observed a statistically significant decrease in active demethylation products in urine, with a final level similar to the level characteristic of healthy children. The level of 5-hmdC in the DNA of the leukocytes in blood of the patient group was significantly lower than that of the control group. Our data suggest that urinary excretion of epigenetic DNA modification may be a marker of pediatric ALL status and a reliable marker of chemotherapy response.

Viral infection-oxidative stress/DNA damage-aberrant DNA methylation: separate or interrelated events responsible for genetic instability and childhood ALL development?

Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates in a single B- or T-lymphocyte progenitor and is characterized by a range of numeric and structural chromosomal aberrations. Although, so far no clear cause can be found for ALL the most commonly recognized and strongest causal factor is infection. However, an interesting question is how viral infection may be responsible for genetic changes that lead to lymphoid cell transformation. A plausible mechanism by which infection might impact the process of leukemogenesis via genetic alteration is through: oxidative stress/DNA damage which is closely linked with inflammation, aberrant expression of AID/ABOBEC family enzymes which may be responsible for massive mutation introduction and alteration of DNA methylation, leading to changes in the expression of hematopoietic genes. In this review we propose several specific molecular mechanisms which link infection with all the above-mentioned processes. The most likely event which links common virus infection with ALL pathogenesis is aberrant expression of AID/APOBEC. This event may be directly responsible for the introduction of point mutations (as the result of cytosine or 5-methylcytosine deamination and formation of G:U or G:T misspairs) as well as changes in DNA methylation status.