Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia.
Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the Emu-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from Emu-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of Foxd3 expression due to an NF-kappaB p50/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-kappaB components in CLL and potentially other B-cell malignancies.
Chen
Shih-Shih
SS
Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
Raval
Aparna
A
Johnson
Amy J
AJ
Hertlein
Erin
E
Liu
Te-Hui
TH
Jin
Victor X
VX
Sherman
Mara H
MH
Liu
Shu-Jun
SJ
Dawson
David W
DW
Williams
Katie E
KE
Lanasa
Mark
M
Liyanarachchi
Sandya
S
Lin
Thomas S
TS
Marcucci
Guido
G
Pekarsky
Yuri
Y
Davuluri
Ramana
R
Croce
Carlo M
CM
Guttridge
Denis C
DC
Teitell
Michael A
MA
Byrd
John C
JC
Plass
Christoph
C
D000818:Animals; D019175:DNA Methylation; D004195:Disease Models, Animal; D018450:Disease Progression; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D051858:Forkhead Transcription Factors; C101757:Foxd3 protein, mouse; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C490393:Tcl1 protein, mouse; D015534:Trans-Activators; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases