| First Author | Balatoni CE | Year | 2009 |
| Journal | Am J Pathol | Volume | 175 |
| Issue | 4 | Pages | 1653-61 |
| PubMed ID | 19717643 | Mgi Jnum | J:153067 |
| Mgi Id | MGI:4360824 | Doi | 10.2353/ajpath.2009.090091 |
| Citation | Balatoni CE, et al. (2009) Epigenetic silencing of Stk39 in B-cell lymphoma inhibits apoptosis from genotoxic stress. Am J Pathol 175(4):1653-61 |
| abstractText | 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 NH(2)-terminal kinase is potentially activated by SPAK and pharmacological inhibition of c-Jun NH(2)-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. |
