Cancer Silencing Cell Death?

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

Although most cases of chronic lymphocytic leukemia (CLL, one of the most common forms of adult leukemia) are sporadic, perhaps 10 to 20% are familial (see Debatin). Noting that aberrant DNA methylation--and thereby abnormal gene silencing--was emerging as a factor in CLL, Raval et al. performed quantitative high-throughput analysis to investigate DNA methylation in the CpG island of DAPK1 (death-associated protein kinase 1). DNA methylation of DAPK1 gene, which encodes a serine/threonine kinase implicated in promoting apoptosis in response to Fas, interferon-, and TNF-, was increased in peripheral blood mononuclear cells and CD19+ B cells from people with CLL compared with that in cells from healthy volunteers. Reverse transcription polymerase chain reaction analysis indicated that DAPK1 expression was decreased in CD19+ CLL cells compared with that in B lymphocytes, and methylation reduced activity of a gene reporter containing a region of the DAPK1 promoter. Genome-wide linkage analysis of a large family with several members with CLL, combined with high-resolution genotyping, identified a 707-kb haplotype on chromosome 9 common to all individuals affected by CLL that included DAPK1. Genomic sequencing identified a single-nucleotide polymorphism (SNP) in the CLL allele that was not found in 383 control tissue samples from Europe and the United States; analysis of 263 CLL tissue samples revealed a single additional CLL case with this SNP. Transcriptional activation of gene reporters suggested that the CLL SNP enhanced binding of a transcriptional suppressor; electrophoretic mobility shift analysis also indicated that the SNP enhanced protein binding. Supershift assays suggested that HOXB7 bound to this region, and transfection of fibroblasts with HOXB7 siRNA led to an increase in DAPK1 expression that was more pronounced with the CLL than the wild-type allele. Thus, the authors concluded that a combination of genetic and epigenetic factors leads to a decrease in DAPK1 expression and that the decrease in DAPK1 activity may increase susceptibility to CLL.

A. Raval, S. M. Tanner, J. C. Byrd, E. B. Angerman, J. D. Perko, S.-S. Chen, B. Hackanson, M. R. Grever, D. M. Lucas, J. J. Matkovic, T. S. Lin, T. J. Kipps, F. Murray, D. Weisenburger, W. Sanger, J. Lynch, P. Watson, M. Jansen, Y. Yoshinaga, R. Rosenquist, P. J. de Jong, P. Coggill, S. Beck, H. Lynch, A. de la Chapelle, C. Plass, Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129, 879-890 (2007). [PubMed]

K.-M. Debatin, Chronic lymphocytic leukemia: Keeping cell death at bay. Cell 129, 853-855 (2007). [PubMed]