Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia

被引:69
|
作者
Chen, Shih-Shih [1 ,2 ,3 ]
Raval, Aparna [1 ,4 ]
Johnson, Amy J. [3 ]
Hertlein, Erin [3 ]
Liu, Te-Hui [1 ,5 ]
Jin, Victor X. [1 ]
Sherman, Mara H. [6 ,7 ]
Liu, Shu-Jun [3 ]
Dawson, David W. [5 ]
Williams, Katie E. [2 ]
Lanasa, Mark [8 ]
Liyanarachchi, Sandya [1 ]
Lin, Thomas S. [2 ]
Marcucci, Guido [1 ,2 ]
Pekarsky, Yuri [1 ]
Davuluri, Ramana [1 ]
Croce, Carlo M. [1 ]
Guttridge, Denis C. [1 ]
Teitell, Michael A. [6 ,7 ]
Byrd, John C. [1 ,3 ]
Plass, Christoph [1 ,9 ]
机构
[1] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Human Canc Genet Program, Ctr Comprehens Canc, Columbus, OH 43210 USA
[2] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA
[3] Ohio State Univ, Div Hematol Oncol, Dept Med, Columbus, OH 43210 USA
[4] Stanford Univ, Dept Oncol, CCSR 2250, Stanford, CA 94305 USA
[5] Childrens Hosp Philadelphia, Dept Infect Dis, Philadelphia, PA 19104 USA
[6] Univ Calif Los Angeles, Inst Mol Biol, Dept Pathol & Lab Med, Broad Stem Cell Res Ctr, Los Angeles, CA 90095 USA
[7] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
[8] Duke Univ, Med Ctr, Div Med Oncol, Dept Med, Durham, NC 27710 USA
[9] German Canc Res Ctr, Div Epigen & Canc Risk, D-69120 Heidelberg, Germany
关键词
CLL; DNA methylation; epigenetics; FOXD3; CPG-ISLAND METHYLATION; DNA METHYLATION; TRANSCRIPTION FACTORS; GENE-EXPRESSION; MOUSE MODEL; RECRUITMENT; REPRESSION; CANCER; FOXD3; TCL-1;
D O I
10.1073/pnas.0906455106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 E mu-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 E mu-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-kappa B 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-kappa B components in CLL and potentially other B-cell malignancies.
引用
收藏
页码:13433 / 13438
页数:6
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