title: Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia.
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.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, The Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43214, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Raval
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Tanner
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Angerman
authors.forename: James D
authors.initials: JD
authors.lastname: Perko
authors.forename: Shih-Shih
authors.initials: SS
authors.lastname: Chen
authors.forename: Björn
authors.initials: B
authors.lastname: Hackanson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Matkovic
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Dennis
authors.initials: D
authors.lastname: Weisenburger
authors.forename: Warren
authors.initials: W
authors.lastname: Sanger
authors.forename: Jane
authors.initials: J
authors.lastname: Lynch
authors.forename: Patrice
authors.initials: P
authors.lastname: Watson
authors.forename: Mary
authors.initials: M
authors.lastname: Jansen
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshinaga
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: de Jong
authors.forename: Penny
authors.initials: P
authors.lastname: Coggill
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.forename: Henry
authors.initials: H
authors.lastname: Lynch
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
mesh_terms: D022981:Allelic Imbalance; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001402:B-Lymphocytes / Q000166:cytology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D064550:Death-Associated Protein Kinases; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D018095:Germ-Line Mutation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D051379:Mice; D010375:Pedigree; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases