Prognostic significance of DNMT3a gene expression and reactive nitrogen species in newly diagnosed Egyptian de novo adult acute myeloid leukemia patients

Abstract

Background

DNA methyltransferase 3a (DNMT3a) gene is a frequently dysregulated epigenetic modifier gene involved in the process of carcinogenesis. Also, there is a dichotomous nature of nitric oxide action with the ability to both promote and repress cancers. There is a host of research work delineating the frequency of DNMT3a mutation in acute myeloid leukemia (AML), but little is known about its level of expression in AML patients or its probable relationship to nitrosative stress. This study aims at the assessment DNMT3a gene expression as well as nitric oxide levels in newly diagnosed adult patients with de novo AML. Moreover, it aims at relating these two variables to other disease features and prognostic indicators as well as treatment outcomes. The study included 45 adult de novo AML patients and 10 healthy control subjects. Measurement of DNMT3a messenger ribonucleic acid (mRNA) transcripts was done by real-time quantitative polymerase chain reaction (RQ-PCR) followed by Sanger sequencing to identify the presence or absence of DNMT3a arginine 882 (R882) mutation. This was followed by the assessment of serum nitrite level as a surrogate marker for nitric oxide radical (NO) using colorimetric methods.

Results

DNMT3a gene expression, as well as serum nitrite levels, were significantly higher among AML cases in relation to controls before chemotherapy with P values of < 0.001 and 0.035, respectively. Dividing patients into low and high expressors in relation to the hotspot mutation demonstrated no difference between the two groups in terms of demographic, clinical, and laboratory characteristics or treatment outcomes.

Conclusion

DNMT3a gene expression is increased among the AML population in relation to normal healthy controls. This may point out the need for the assessment of the influence of this gene expression on methylcytosine content of tumor samples with the subsequent implementation of hypomethylating agents as a line of therapy in cases exhibiting excessive hypermethylation.