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Open Access Research article

Aberrant methylation of the M-type phospholipase A2 receptor gene in leukemic cells

Mario Menschikowski1*, Uwe Platzbecker2, Albert Hagelgans1, Margot Vogel1, Christian Thiede2, Claudia Schönefeldt2, Renate Lehnert1, Graeme Eisenhofer1 and Gabriele Siegert1

Author Affiliations

1 Institut für Klinische Chemie und Laboratoriumsmedizin, Technische Universität Dresden, Fetscherstrasse 74, D-01307, Dresden, Germany

2 Medizinische Klinik und Poliklinik I, Technische Universität Dresden, Dresden, Germany

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BMC Cancer 2012, 12:576  doi:10.1186/1471-2407-12-576

Published: 5 December 2012

Abstract

Background

The M-type phospholipase A2 receptor (PLA2R1) plays a crucial role in several signaling pathways and may act as tumor-suppressor. This study examined the expression and methylation of the PLA2R1 gene in Jurkat and U937 leukemic cell lines and its methylation in patients with myelodysplastic syndrome (MDS) or acute leukemia.

Methods

Sites of methylation of the PLA2R1 locus were identified by sequencing bisulfite-modified DNA fragments. Methylation specific-high resolution melting (MS-HRM) analysis was then carried out to quantify PLA2R1 methylation at 5`-CpG sites identified with differences in methylation between healthy control subjects and leukemic patients using sequencing of bisulfite-modified genomic DNA.

Results

Expression of PLA2R1 was found to be completely down-regulated in Jurkat and U937 cells, accompanied by complete methylation of PLA2R1 promoter and down-stream regions; PLA2R1 was re-expressed after exposure of cells to 5-aza-2´-deoxycytidine. MS-HRM analysis of the PLA2R1 locus in patients with different types of leukemia indicated an average methylation of 28.9% ± 17.8%, compared to less than 9% in control subjects. In MDS patients the extent of PLA2R1 methylation significantly increased with disease risk. Furthermore, measurements of PLA2R1 methylation appeared useful for predicting responsiveness to the methyltransferase inhibitor, azacitidine, as a pre-emptive treatment to avoid hematological relapse in patients with high-risk MDS or acute myeloid leukemia.

Conclusions

The study shows for the first time that PLA2R1 gene sequences are a target of hypermethylation in leukemia, which may have pathophysiological relevance for disease evolution in MDS and leukemogenesis.

Keywords:
Phospholipase A2 receptor; DNA methylation; High resolution melting analysis; Leukemia