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Originally published online as doi:10.2353/ajpath.2009.090091 on August 28, 2009

Published online before print August 28, 2009
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(American Journal of Pathology. 2009;175:1653-1661.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090091

Epigenetic Silencing of Stk39 in B-Cell Lymphoma Inhibits Apoptosis from Genotoxic Stress

Cynthia E. Balatoni*, David W. Dawson*{dagger}, Jane Suh*, Mara H. Sherman{ddagger}, Grant Sanders*, Jason S. Hong*, Matthew J. Frank*, Cindy S. Malone§, Jonathan W. Said* and Michael A. Teitell*{dagger}{ddagger}¶||

From the Department of Pathology and Laboratory Medicine,* the Jonsson Comprehensive Cancer Center,{dagger} and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles; the Department of Biology,§ California State University Northridge, Northridge; and the Molecular Biology Institute{ddagger} and California NanoSystems Institute,|| UCLA, Los Angeles, California

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.


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