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.
Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
Leukemia. 2014 Apr;28(4):787-93. doi: 10.1038/leu.2013.270. Epub 2013 Sep 18.
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.
异常的 DNA 启动子甲基化与相关基因沉默是急性淋巴细胞白血病（ALL）中常见的表观遗传异常，与生存不良相关。我们已经确定了一组跨膜酪氨酸磷酸酶蛋白作为 ALL 和高级别 B 细胞淋巴瘤中高甲基化的靶标，并证明这种异常甲基化与转录表达相关。PTPRG 在 63%的 ALL 样本中发生甲基化，PTPRK 在 47%的样本中发生甲基化，PTPRM 在 64%的样本中发生甲基化，PTPRO 在 54%的样本中发生甲基化，大多数 ALL 样本在多个磷酸酶基因座发生甲基化。PTPRK 启动子甲基化与队列中总生存率降低相关。在白血病细胞中恢复磷酸酶转录本水平（其中磷酸酶转录本被沉默），可降低细胞增殖、抑制集落形成并增加对细胞毒化疗的敏感性。这些生物学变化与磷酸化 Erk1/2、Akt、STAT3 和 STAT5 水平降低相关，提示转录本重新表达后具有功能性磷酸酶活性。磷酸酶启动子的甲基化可被地西他滨和组蛋白去乙酰化酶抑制剂逆转，提示在淋巴恶性肿瘤中，PTPRK 介导的细胞信号通路可能可以通过表观遗传治疗来靶向。
