Downregulation of Death-Associated Protein Kinase 1 (DAPK1) in Chronic Lymphocytic Leukemia

Aparna Raval, Stephan M. Tanner, John C. Byrd, Elizabeth B. Angerman, James D. Perko, Shih Shih Chen, Björn Hackanson, Michael R. Grever, David M. Lucas, Jennifer J. Matkovic, Thomas S. Lin, Thomas J. Kipps, Fiona Murray, Dennis Weisenburger, Warren Sanger, Jane Lynch, Patrice Watson, Mary Jansen, Yuko Yoshinaga, Richard RosenquistPieter J. de Jong, Penny Coggill, Stephan Beck, Henry Lynch, Albert de la Chapelle, Christoph Plass

Research output: Contribution to journalArticle

286 Scopus citations

Abstract

The heritability of B cell chronic lymphocytic leukemia (CLL) is relatively high; however, no predisposing mutation has been convincingly identified. We show that loss or reduced expression of death-associated protein kinase 1 (DAPK1) underlies cases of heritable predisposition to CLL and the majority of sporadic CLL. Epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. Furthermore, we defined a disease haplotype, which segregates with the CLL phenotype in a large family. DAPK1 expression of the CLL allele is downregulated by 75% in germline cells due to increased HOXB7 binding. In the blood cells from affected family members, promoter methylation results in additional loss of DAPK1 expression. Thus, reduced expression of DAPK1 can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CLL phenotype.

Original languageEnglish (US)
Pages (from-to)879-890
Number of pages12
JournalCell
Volume129
Issue number5
DOIs
StatePublished - Jun 1 2007

Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Raval, A., Tanner, S. M., Byrd, J. C., Angerman, E. B., Perko, J. D., Chen, S. S., Hackanson, B., Grever, M. R., Lucas, D. M., Matkovic, J. J., Lin, T. S., Kipps, T. J., Murray, F., Weisenburger, D., Sanger, W., Lynch, J., Watson, P., Jansen, M., Yoshinaga, Y., ... Plass, C. (2007). Downregulation of Death-Associated Protein Kinase 1 (DAPK1) in Chronic Lymphocytic Leukemia. Cell, 129(5), 879-890. https://doi.org/10.1016/j.cell.2007.03.043