Abstract
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are characterized by genomic instability, which may arise from the global hypomethylation of the DNA. The active DNA demethylation process may be linked with aberrant methylation and can be involved in leukemogenesis. The levels of 5-methylcytosine oxidation products were analyzed in minimally invasive material: the cellular DNA from peripheral blood cells and urine of patients with AML and MDS along with the control group, using isotope-dilution two-dimensional ultra-performance liquid chromatography with tandem mass spectrometry. The receiver operating characteristic curve analysis was used for the assessment of the ability to discriminate patients’ groups from the control group, and AML from MDS. The most diagnostically useful for discriminating AML patients from the control group was the urinary excretion of 5-hydroxymethylcytosine (AUC = 0.918, sensitivity: 85%, and specificity: 97%), and 5-(hydroxymethyl)-2′-deoxyuridine (0.873, 74%, and 92%), while for MDS patients 5-(hydroxymethyl)-2′-deoxycytidine in DNA (0.905, 82%, and 98%) and urinary 5-hydroxymethylcytosine (0.746, 66%, and 92%). Multi-factor models of classification trees allowed the correct classification of patients with AML and MDS in 95.7% and 94.7% of cases. The highest prognostic value of the analyzed parameters in predicting the transformation of MDS into AML was observed for 5-carboxy-2′-deoxycytidine (0.823, 80%, and 97%) and 5-(hydroxymethyl)-2′-deoxyuridine (0.872, 100%, and 75%) in DNA. The presented research proves that the intermediates of the active DNA demethylation pathway determined in the completely non-invasive (urine) or minimally invasive (blood) material can be useful in supporting the diagnostic process of patients with MDS and AML. The possibility of an early identification of a group of MDS patients with an increased risk of transformation into AML is of particular importance.
Highlights
Acute myeloid leukemia (AML) is the most common acute leukemia in adults, in particular, those over 60 years old; it accounts for 15–20% of cases in children
The diagnosis of Myelodysplastic syndromes (MDS) is based on the identification of cytopenia of one, two, or three erythroid, granulocytic, or megakaryocytic cell lines and bone marrow cell dysplasia (the detailed morphological classification is based on the 2008 World Health Organization (WHO) version [3] revised in 2016 [4])
Owing to a plethora of the aforementioned factors suspected of shaping the epigenetic landscape, we aimed to investigate the diagnostic value and prognostic power of active DNA demethylation pathway intermediates in AML and MDS
Summary
Acute myeloid leukemia (AML) is the most common acute leukemia in adults, in particular, those over 60 years old; it accounts for 15–20% of cases in children. This genetically heterogeneous disease is characterized by the malignant clonal proliferation of immature myeloid cells in the bone marrow, peripheral blood, and sometimes peripheral organs. According to the WHO guidelines, the current classification of AML relies on cytomorphology, immunophenotyping, cytogenetics, and molecular genetics. Such an interdisciplinary approach is necessary to increase the quality of prognostication and there is still space to introduce new diagnostic parameters [8]. Major limitations in the current diagnostic approach to MDS/AML lay in the limited reproducibility of morphological analysis of dysplasia and in the weak specificity of dysplastic changes [12,13]
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