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Epigenetic inactivation of the ERK inhibitor Spry2 in B-cell diffuse lymphomas

Oncogene volume 27, pages 4969–4972 (2008)Cite this article

Abstract

Spry2 has been characterized as a negative regulator of the extracellular-regulated kinase (ERK) pathway. In this study we analysed whether epigenetic alterations of hSpry2 promoter occur in human lymphoid/hematopoietic malignancies. Our results revealed that hSpry2 promoter was hypermethylated in the HT cell line derived from a B-cell diffuse lymphoma, which correlated with decreased hSpry2 expression. We detected deregulation of the ERK pathway in these cells, but not in other blood cell lines expressing hSpry2. In addition, the ectopic overexpression of hSpry2 in HT cells drastically reduced the activation of ERK upon phorbol 12-myristate-13-acetate stimulation. Nude mice inoculated with HT mock cells developed tumors seven times larger than those from HT-hSpry2-transfected cells. We found hypermethylation of hSpry2 promoter in 37% (26 cases out of 71) of primary tumors from patients with B-cell diffuse lymphoma but none in normal B lymphocytes from 37 healthy individuals. Finally, we detected that hSpry2 promoter hypermethylation was associated with a significant decrease in the 5-year survival rate. These data suggest that hSpry2 could be important in lymphoid malignancies.

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Acknowledgements

We thank Dr A Toraño and Dr M Domínguez for the comments and help to recruit the healthy volunteers. AS was recipient of a fellowship from the Instituto de Salud Carlos III. This work was supported by grants SAF2006-04247 from the Ministerio de Educación y Ciencia, Spain; FMMA-2005 from the Fundación Mutua Madrileña Automovilista; BM04/179-02 from the Fundació ‘la Caixa’; GR/SAL/0291/2004 from the Comunidad de Madrid, Spain and RETICS from the Instituto de Salud Carlos III (Red Temática de Investigación Cooperativa en Cáncer) to JMR; and the Health (FIS, FIS01-04) and Science (I+D+I) departments of the Spanish Government to ME and the Spanish Association Against Cancer (AECC) to JMR and ME.

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Author notes

  1. M Esteller and J M Rojas: These authors contributed equally to this work.

Authors and Affiliations

  1. Unidad de Biología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain

    A Sánchez, N Martinez, J L Oliva & J M Rojas

  2. Molecular Pathology Programme, Cancer Epigenetics Laboratory, Spanish National Cancer Center (CNIO), Madrid, Spain

    F Setién, M Herranz, M-F Fraga, M Alaminos & M Esteller

Authors
  1. A Sánchez
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  2. F Setién
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  3. N Martinez
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  4. J L Oliva
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  5. M Herranz
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  6. M-F Fraga
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  7. M Alaminos
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  8. M Esteller
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  9. J M Rojas
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Corresponding author

Correspondence to J M Rojas.

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

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Sánchez, A., Setién, F., Martinez, N. et al. Epigenetic inactivation of the ERK inhibitor Spry2 in B-cell diffuse lymphomas. Oncogene 27, 4969–4972 (2008). https://doi.org/10.1038/onc.2008.129

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