德國和美國研究人員以老鼠為對象進行的實驗發(fā)現(xiàn),，幼鼠最早在3個月大時就會出現(xiàn)一種與日后患白血病有關的基因甲基化現(xiàn)象。如果這種現(xiàn)象在人體實驗中也得到證實,，將有望尋找到篩查患癌高危人群的新方法,。
研究小組在新一期美國《國家科學院學報》上介紹說,，在許多類型的癌癥中,，癌細胞中的某些基因會被甲基化,，從而無法正常表達。這種現(xiàn)象尤其常見于一些對癌細胞生長起到抑制作用的基因,。研究人員希望查明其中的具體機制,，比如這種甲基化是在癌癥發(fā)病的哪個階段出現(xiàn)的。
研究人員利用基因改良工程培育先天罹患慢性淋巴細胞白血病的實驗鼠,。他們從老鼠一出生就開始定期監(jiān)測其基因的變化情況,。結果發(fā)現(xiàn)，患病老鼠的基因在其出生3個月后就出現(xiàn)了與癌癥相關的甲基化,，而老鼠所患癌癥的具體癥狀至少要到其出生后的第13個月才逐漸顯現(xiàn),。
研究還發(fā)現(xiàn)，實驗鼠的基因甲基化模式與人類白血病患者的基因甲基化模式非常相似,。“既然老鼠的首次甲基化出現(xiàn)得那么早,，我們下一步會研究人類是否也這樣”，研究負責人克里斯托弗·普拉斯說,，果真如此的話，將來就可以在患癌高危人群中進行基因甲基化檢測,，以便早發(fā)現(xiàn),、早治療。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS July 28, 2009, doi: 10.1073/pnas.0906455106
Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia
Shih-Shih Chena,b,c, Aparna Ravala,d, Amy J. Johnsonc, Erin Hertleinc, Te-Hui Liua,e, Victor X. Jina, Mara H. Shermanf, Shu-Jun Liuc, David W. Dawsone, Katie E. Williamsb, Mark Lanasag, Sandya Liyanarachchia, Thomas S. Linb, Guido Marcuccia,b, Yuri Pekarskya, Ramana Davuluria, Carlo M. Crocea, Denis C. Guttridgea, Michael A. Teitellf, John C. Byrda,c,1,2 and Christoph Plassa,h,1,2
aDepartment of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,
bDepartment of Molecular Genetics,
cDivision of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;
dDepartment of Oncology, CCSR 2250, Stanford University, Stanford, CA 94305;
eDepartment of Infectious Disease, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
fMolecular Biology Institute, Department of Pathology and Laboratory Medicine, Broad Stem Cell Research Center, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;
gDepartment of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710; and
hDivision of Epigenomics and Cancer Risk, German Cancer Research Center, 69120 Heidelberg, Germany
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 Eμ-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 Eμ-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-κB 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-κB components in CLL and potentially other B-cell malignancies.
