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Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2007 Jun 01; Vol. 13 (11), pp. 3174-81. - Publication Year :
- 2007
-
Abstract
- Purpose: Previous studies in our laboratory have shown the progressive methylation and suppression of the gene encoding protein tyrosine phosphatase, PTPRO, in the livers of rats fed a methyl-deficient diet that induces hepatocarcinogenesis. Subsequently, we observed the methylation of PTPRO in primary human lung tumors and also showed its potential tumor suppressor characteristics. The present study was undertaken to investigate whether the truncated form of PTPRO (PTPROt), specifically expressed in naïve B lymphocytes, was also methylated and suppressed in chronic lymphocytic leukemia (CLL), a disease generally affecting B lymphocytes.<br />Experimental Design and Results: Initial screening showed that 60% of the 52 CLL samples analyzed using methylation-specific PCR assay were methylated compared with B lymphocytes from normal individuals, which were not methylated. The expression of PTPROt, as measured by semiquantitative reverse transcription-PCR, inversely correlated with methylation in the few samples tested. Analysis of additional samples (n = 50) by combined bisulfite restriction analysis showed that the PTPRO CpG island was methylated in 82% of patients with CLL compared with B lymphocytes from normal individuals. Furthermore, overall expression of PTPRO was reduced in CLL relative to normal lymphocytes. The PTPRO gene was also suppressed by methylation in the CLL cell line WaC3CD5, where it could be reactivated upon treatment with the DNA hypomethylating agent 5-AzaC. Ectopic expression of PTPROt in a nonexpressing cell line increased growth inhibition with fludarabine treatment, a therapy commonly used for CLL.<br />Conclusion: This study reveals the potential role of PTPRO methylation and silencing in CLL tumorigenesis and also provides a novel molecular target in the epigenetic therapy.
- Subjects :
- B-Lymphocytes metabolism
Epigenesis, Genetic
Humans
Membrane Proteins metabolism
Models, Biological
Polymerase Chain Reaction
Protein Tyrosine Phosphatases physiology
Receptor-Like Protein Tyrosine Phosphatases, Class 3
Reverse Transcriptase Polymerase Chain Reaction
Sulfites pharmacology
Vidarabine analogs & derivatives
Vidarabine pharmacology
DNA Methylation
Gene Expression Regulation, Neoplastic
Gene Silencing
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Leukemia, Lymphocytic, Chronic, B-Cell therapy
Membrane Proteins physiology
Protein Tyrosine Phosphatases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 13
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 17545520
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-06-1720