德国和美国研究人员以老鼠为对象进行的实验发现，幼鼠最早在3个月大时就会出现一种与日后患白血病有关的基因甲基化现象。如果这种现象在人体实验中也得到证实，将有望寻找到筛查患癌高危人群的新方法。
研究小组在新一期美国《国家科学院学报》上介绍说，在许多类型的癌症中，癌细胞中的某些基因会被甲基化，从而无法正常表达。这种现象尤其常见于一些对癌细胞生长起到抑制作用的基因。研究人员希望查明其中的具体机制，比如这种甲基化是在癌症发病的哪个阶段出现的。
研究人员利用基因改良工程培育先天罹患慢性淋巴细胞白血病的实验鼠。他们从老鼠一出生就开始定期监测其基因的变化情况。结果发现，患病老鼠的基因在其出生3个月后就出现了与癌症相关的甲基化，而老鼠所患癌症的具体症状至少要到其出生后的第13个月才逐渐显现。
研究还发现，实验鼠的基因甲基化模式与人类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现得那么早，我们下一步会研究人类是否也这样”，研究负责人克里斯托弗·普拉斯说，果真如此的话，将来就可以在患癌高危人群中进行基因甲基化检测，以便早发现、早治疗。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
