Global methylation profiling in TCL1 transgenic mice reveals novel targets of DNA hypermethylation in mature B cell lymphomas Free

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The full range of epigenetic modifications associated with malignant transformation in germinal center (GC) B cell lymphomas remains to be defined. In this study we have used restriction landmark genomic scanningto identify more than 100 genes that undergo tumor-associated DNA hypermethylation in a TCL1 transgenic mouse model of aggressive GC and marginal zone B cell lymphomas. Multiple genes undergoing DNA hypermethylation were shown to have decreased expression in TCL1 transgenic tumors, including the Eph receptor family member Epha7.  EPHA7 was also found to bea target of DNA hypermethylation and gene silencing in a majority of human GC B cell non-Hodgkin lymphomas. Normal peripheral lymphocytes were shown to express a splice variant of EPHA7 resulting in a truncated/secreted protein with the potential to block EphA/ephrin signaling under normal physiologic circumstances; this activity is potentially abrogated through epigenetic silencing of EPHA7 in GC B cell lymphomas. These data provide the first set of hypermethylated genes with the potential to complement TCL1-mediated GC B cell transformation and spread.