title: Aberrant methylation of the M-type phospholipase A(2) receptor gene in leukemic cells.
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.
authors.affiliation: Institut für Klinische Chemie und Laboratoriumsmedizin, Technische Universität Dresden, Fetscherstrasse 74, D-01307, Dresden, Germany. Mario.Menschikowski@uniklinikum-dresden.de
authors.forename: Mario
authors.initials: M
authors.lastname: Menschikowski
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.forename: Albert
authors.initials: A
authors.lastname: Hagelgans
authors.forename: Margot
authors.initials: M
authors.lastname: Vogel
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Claudia
authors.initials: C
authors.lastname: Schönefeldt
authors.forename: Renate
authors.initials: R
authors.lastname: Lehnert
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siegert
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics; D054507:Receptors, Phospholipase A2 / Q000235:genetics* / Q000378:metabolism; D020298:U937 Cells; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; C516360:PLA2R1 protein, human; D054507:Receptors, Phospholipase A2; D000077209:Decitabine; D001374:Azacitidine