Giotopoulos George, McCormick Carol, Cole Clare, Zanker Abigail, Jawad Mays, Brown Robert, Plumb Mark
Department of Genetics, University of Leicester, Leicester, United Kingdom.
Exp Hematol. 2006 Nov;34(11):1462-70. doi: 10.1016/j.exphem.2006.06.008.
To examine DNA methylation in mouse hemopoiesis before and after in vivo exposure to a leukemogenic dose of x-rays, and address whether methylation levels are associated with the relative radiosensitivity of tissues in vivo.
The methylation status of control CBA/H and C57BL/6 mouse tissues before and after exposure to 3-Gy x-rays, and myeloid and lymphoid leukemias and lymphomas, was assessed by the direct analysis of the 5-methylcytosine (5-(Me)C) content of DNA, and by Southern blot analysis of genomic repeat sequences.
The DNA 5-(Me)C content of bone marrow is 15% lower than spleen. Together with the analyses of stem (myeloid) and progenitor (lymphoid) leukemias and lymphomas, we found a trend of increasing methylation during hemopoietic differentiation. Exposure to x-rays induced greater cell death in the hypomethylated bone marrow (>80%) than spleen (50%) in vivo, supporting the observed correlation found between methylation status and radiosensitivity of other high-turnover hierarchical tissues. Furthermore, there was an 8% DNA 5-(Me)C content decrease in bone marrow after in vivo exposure to 3-Gy x-rays, but this was genotype dependent, being observed in AML-susceptible (CBA/H) but not AML-resistant (C57BL/6) inbred mice.
Together these data suggest that methylation status may be related to the relative radiosensitivity of high-turnover hierarchical tissues such as bone marrow and that radiation-induced DNA hypomethylation has a role in radiation leukemogenesis.
研究小鼠在体内暴露于致白血病剂量的X射线前后造血过程中的DNA甲基化情况，并探讨甲基化水平是否与体内组织的相对放射敏感性相关。
通过直接分析DNA的5-甲基胞嘧啶（5-(Me)C）含量以及对基因组重复序列进行Southern印迹分析，评估对照CBA/H和C57BL/6小鼠组织在暴露于3 Gy X射线前后以及髓系和淋巴系白血病及淋巴瘤中的甲基化状态。
骨髓的DNA 5-(Me)C含量比脾脏低15%。结合对干细胞（髓系）和祖细胞（淋巴系）白血病及淋巴瘤的分析，我们发现在造血分化过程中甲基化有增加的趋势。在体内，暴露于X射线后，低甲基化的骨髓（>80%）比脾脏（50%）诱导了更多的细胞死亡，这支持了在甲基化状态与其他高周转率分级组织的放射敏感性之间观察到的相关性。此外，体内暴露于3 Gy X射线后，骨髓中的DNA 5-(Me)C含量降低了8%，但这取决于基因型，在AML易感（CBA/H）而非AML抗性（C57BL/6）近交小鼠中观察到。
这些数据共同表明，甲基化状态可能与骨髓等高周转率分级组织的相对放射敏感性有关，并且辐射诱导的DNA低甲基化在辐射白血病发生中起作用。
