Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia.
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.
Raval
Aparna
A
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.
Tanner
Stephan M
SM
Byrd
John C
JC
Angerman
Elizabeth B
EB
Perko
James D
JD
Chen
Shih-Shih
SS
Hackanson
Björn
B
Grever
Michael R
MR
Lucas
David M
DM
Matkovic
Jennifer J
JJ
Lin
Thomas S
TS
Kipps
Thomas J
TJ
Murray
Fiona
F
Weisenburger
Dennis
D
Sanger
Warren
W
Lynch
Jane
J
Watson
Patrice
P
Jansen
Mary
M
Yoshinaga
Yuko
Y
Rosenquist
Richard
R
de Jong
Pieter J
PJ
Coggill
Penny
P
Beck
Stephan
S
Lynch
Henry
H
de la Chapelle
Albert
A
Plass
Christoph
C
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
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