DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia

W. S. Stevenson, O. G. Best, A. Przybylla, Q. Chen, N. Singh, M. Koleth, S. Pierce, T. Kennedy, W. Tong, S. Q. Kuang, G. Garcia-Manero

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Aberrant DNA promoter methylation with associated gene silencing is a common epigenetic abnormality in acute lymphoblastic leukaemia (ALL) and is associated with poor survival. We have identified a family of transmembrane tyrosine phosphatase proteins as targets of hypermethylation in ALL and high-grade B cell lymphoma and demonstrated that this abnormal methylation correlates with transcript expression. PTPRG was methylated in 63% of ALL samples, PTPRK in 47%, PTPRM in 64% and PTPRO in 54% of cases, with most ALL samples containing methylation at multiple phosphatase loci. PTPRK promoter methylation was associated with a decreased overall survival in the cohort. Restoration of PTPRK transcript levels in leukaemia cells, where phosphatase transcript was silenced, reduced cell proliferation, inhibited colony formation and increased sensitivity to cytotoxic chemotherapy. These biological changes were associated with a reduction in levels of phosphorylated Erk1/2, Akt, STAT3 and STAT5 suggesting functional phosphatase activity after transcript re-expression. Methylation of the phosphatase promoters was reversible with decitabine and a histone deacetylase inhibitor, suggesting that PTPRK-mediated cell signalling pathways may be targeted with epigenetic therapies in lymphoid malignancy.
Original languageEnglish
Pages (from-to)787-793
Number of pages7
JournalLeukemia
Volume28
Issue number4
DOIs
Publication statusPublished - Apr 2014
Externally publishedYes

Keywords

  • Adolescent Adult Aged Cell Line, Tumor Cell Proliferation CpG Islands *DNA Methylation Humans Janus Kinase 1/genetics Middle Aged Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics Promoter Regions, Genetic Proportional Hazards Models Protein Tyrosine Phosphatases/*genetics Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics STAT3 Transcription Factor/metabolism STAT5 Transcription Factor/metabolism
  • PTPRO
  • PTPRM
  • non-Hodgkin lymphoma
  • PTPRK
  • PTPRG

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