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

Oncogene volume 26, pages 4243–4252 (2007)Cite this article

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.

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Acknowledgements

This work was supported by the NIH Grants T32CA009120 (DWD), T32A107126 (RRS) T32CA09056 (SWF), HD041451 (YM), PNEY018228, R01CA90571, R01CA107300 and R01GM073981 (MAT), by the Margaret E Early Medical Research Trust, by CMISE, a NASA URETI Institute (NCC 2-1364) (MAT) and by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (HCM). MAT is a Scholar of the Leukemia and Lymphoma Society.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    D W Dawson, J S Hong, R R Shen, S W French, J J Troke, D Gui, J Said & M A Teitell

  2. Division of Human Cancer Genetics, Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA

    Y-Z Wu, S-S Chen & C Plass

  3. Department of Human Genetics, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    M Regelson & Y Marahrens

  4. Laboratory of Immunopathology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Rockville, MD, USA

    H C Morse III

  5. Molecular Biology Institute, Institute for Stem Cell Biology and Medicine, California NanoSystems Institute, Institute for Cell Mimetic Studies and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA

    M A Teitell

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  1. D W Dawson
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  2. J S Hong
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Correspondence to M A Teitell.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Dawson, D., Hong, J., Shen, R. et al. Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas. Oncogene 26, 4243–4252 (2007). https://doi.org/10.1038/sj.onc.1210211

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