Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas

Abstract

Most human lymphomas originate from transformed germinal center (GC) B lymphocytes. While activating mutations and translocations of MYC, BCL2 and BCL6 promote specific GC lymphoma subtypes, other genetic and epigenetic modifications that contribute to malignant progression in the GC remain poorly defined. Recently, aberrant expression of the TCL1 proto-oncogene was identified in major GC lymphoma subtypes. TCL1 transgenic mice offer unique models of both aggressive GC and marginal zone B-cell lymphomas, further supporting a role for TCL1 in B-cell transformation. Here, restriction landmark genomic scanning was employed to discover tumor-associated epigenetic alterations in malignant GC and marginal zone B-cells in TCL1 transgenic mice. Multiple genes were identified that underwent DNA hypermethylation and decreased expression in TCL1 transgenic tumors. Further, we identified a secreted isoform of EPHA7, a member of the Eph family of receptor tyrosine kinases that are able to influence tumor invasiveness, metastasis and neovascularization. EPHA7 was hypermethylated and repressed in both mouse and human GC B-cell non-Hodgkin lymphomas, with the potential to influence tumor progression and spread. These data provide the first set of hypermethylated genes with the potential to complement TCL1-mediated GC B-cell transformation and spread.

Pathogenesis of follicular lymphoma

“…The authors proposed a model in which soluble EPHA7 binds EPHA2 on lymphoma cell surfaces and prevents activation of signaling through ERK as well as other SRC kinases. They further showed that EPHA7 expression was absent by immunohistochemistry in 72% of FL cases on a tissue microarray and suggested that absence of protein expression occurred through genomic deletions as well as promoter methylation, corroborating earlier findings from Dawson et al (46).…”

Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma

“…These results are in line with data from earlier studies, describing silencing of EPHA7 and DAPK1 in related B-cell lymphomas. 40,41 MMP9 was predominantly hypermethylated in CHLNS and may reflect the sclerotic morphology of this lymphoma suggesting a low expression of matrix metalloproteinases. Hierarchical cluster analysis of these 22 CpG demonstrated that PMLBCL and CHLNS are readily distinguished, while MGZL shows overlap with both groups.…”

Mining the cancer genome uncovers therapeutic activity of EphA7 against lymphoma

“…In lymphoma we observed loss of EPHA7 expression by deletion and/ or epigenetic silencing in ~70% of cases. Specifically, EPHA7 is inactivated in FL, in in marginal zone B-cell lymphomas, 24 in diffuse large B-cell (DLBCL) and in HIV-associated Burkitt lymphoma (BL). 1 Epigenetic silencing of EPHA7 has been reported in adult B-ALL and in solid tumors, including colorectal and prostate carcinoma.…”

“…EPHA7 is remarkable for its expression of short splice variants that have been reported to act as dominant-negative inhibitors of the full-length receptors. 23,24 The role of EPH signaling in cancer is quite unclear, and some reports suggest oncogenic activity for certain receptors, while others…”