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Abstract
Acute lymphoblastic leukaemia (ALL) is the most common form of paediatric cancer and epigenetic aberrations are determinants of leukaemogenesis. The aim of this study was to investigate the methylation degree of a distinct phospholipase A2 receptor 1 (PLA2R1) promoter region in paediatric ALL patients and to evaluate its relevance as new biomarker for monitoring treatment response and burden of residual disease. The impact of PLA2R1 re-expression on proliferative parameters was assessed in vitro in Jurkat cells with PLA2R1 naturally silenced by DNA methylation. Genomic DNA was isolated from bone marrow (BM) and peripheral blood (PB) of 44 paediatric ALL patients. PLA2R1 methylation was analysed using digital PCR and compared to 20 healthy controls. Transfected Jurkat cells were investigated using cell growth curve analysis and flow cytometry. PLA2R1 was found hypermethylated in BM and PB from pre-B and common ALL patients, and in patients with the disease relapse. PLA2R1 methylation decreased along with leukaemic blast cell reduction during ALL induction treatment. In vitro analysis revealed an anti-proliferative phenotype associated with PLA2R1 re-expression, suggesting a tumour-suppressive function of PLA2R1. Collected data indicates that PLA2R1 promoter methylation quantitation can be used as biomarker for ALL induction treatment control, risk stratification, and early detection of ALL relapse.
Highlights
Acute Lymphoblastic Leukaemia (ALL) is the most frequent form of childhood cancer worldwide[1,2]
To investigate the effect of phospholipase A2 receptor 1 (PLA2R1) in childhood Acute lymphoblastic leukaemia (ALL), the PLA2R1 promoter methylation status was analysed by droplet digital polymerase chain reaction in peripheral blood (PB) samples and bone marrow (BM) aspirates of children with ALL and acute myeloid leukaemia (AML)
The PLA2R1 promoter was found to be hypermethylated in BM aspirates and PB samples of patients diagnosed with different childhood ALL subtypes, which makes the PLA2R1 methylation a suitable biomarker for the monitoring of treatment response in ALL patients
Summary
Acute Lymphoblastic Leukaemia (ALL) is the most frequent form of childhood cancer worldwide[1,2]. Our study provided evidence that PLA2R1 promoter methylation is inversely correlated with PLA2R1 expression in the human T lymphocyte acute leukaemia (Jurkat) cell line[19], which is extensively used to investigate ALL20–22. Based on these previous findings, the aim of the present study was to investigate the following: (i) whether the PLA2R1 promoter is hypermethylated in patients with childhood ALL at diagnosis in comparison to healthy individuals; (ii) whether the PLA2R1 promoter methylation in blood leukocyte DNA can be used as a biomarker for treatment response and control of residual disease. The effect of PLA2R1 expression on cell proliferation and apoptosis/necrosis of Jurkat cells as a cell model for childhood ALL was assessed
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