Epigenetic silencing of Stk39 in B-cell lymphoma inhibits apoptosis from genotoxic stress

Cynthia E. Balatoni, David W. Dawson, Jane Suh, Mara H. Sherman, Grant Sanders, Jason S. Hong, Matthew J. Frank, Cindy S. Malone, Jonathan W. Said, Michael A. Teitell

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16 Scopus citations

Abstract

B-cell lymphomas, the most frequent human immune system malignancies, often contain dysregulated TCL1 oncogene expression. TCL1 transgenic (TCL1-tg) mice develop a spectrum of B-cell malignancies, supporting an oncogenic role for TCL1 in B cells. Our prior global survey of DNA methylation patterns in TCL1-tg B-cell lymphomas identified many lymphoma-specific candidate hypermethylated genes, including Stk39. The Stk39 encoded protein, sterile 20-like-related proline-alanine-rich kinase (SPAK), regulates cell stress responses, and microarray studies identified reduced SPAK expression in metastatic prostate and treatment-resistant breast cancers, suggesting that its loss may have a role in cancer progression. Here we identified DNA hypermethylation and SPAK silencing in TCL1-tg B-cell lymphomas and SPAK silencing without DNA methylation in multiple subtypes of human B-cell lymphomas. SPAK knockdown by shRNA protected B cells from caspase-dependent apoptosis induced by DNA double-strand breaks but not apoptosis in response to osmotic or oxidative cell stressors. Caspase 3 activation by cleavage was impaired with SPAK repression in DNA damaged B cells. Interestingly, c-Jun NH2-terminal kinase is potentially activated by SPAK and pharmacological inhibition of c-Jun NH2-terminal kinase in SPAK-expressing B cells recapitulated the cell-protective phenotype of SPAK knockdown. Taken together, these data indicate that SPAK loss in B-cell lymphomas promotes increased cell survival with DNA damage and provides a potential mechanism for increased resistance to genotoxic stress in cancer.

Original languageEnglish (US)
Pages (from-to)1653-1661
Number of pages9
JournalAmerican Journal of Pathology
Volume175
Issue number4
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Balatoni, C. E., Dawson, D. W., Suh, J., Sherman, M. H., Sanders, G., Hong, J. S., Frank, M. J., Malone, C. S., Said, J. W., & Teitell, M. A. (2009). Epigenetic silencing of Stk39 in B-cell lymphoma inhibits apoptosis from genotoxic stress. American Journal of Pathology, 175(4), 1653-1661. https://doi.org/10.2353/ajpath.2009.090091