title: DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia.
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.
authors.affiliation: 1] Department of Haematology, Royal North Shore Hospital, Pathology North, Sydney, Australia [2] Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
authors.forename: W S
authors.initials: WS
authors.lastname: Stevenson
authors.affiliation: Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
authors.forename: O G
authors.initials: OG
authors.lastname: Best
authors.affiliation: Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Przybylla
authors.affiliation: 1] Department of Haematology, Royal North Shore Hospital, Pathology North, Sydney, Australia [2] Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Haematology, Royal North Shore Hospital, Pathology North, Sydney, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Haematology, Royal North Shore Hospital, Pathology North, Sydney, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Koleth
authors.affiliation: Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pierce
authors.affiliation: Department of Haematology, Royal North Shore Hospital, Pathology North, Sydney, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Kennedy
authors.affiliation: Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Tong
authors.affiliation: Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S-Q
authors.initials: SQ
authors.lastname: Kuang
authors.affiliation: Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C489852:PTPRK protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
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