Lieberman S A, Hines M D, Bergsagel P L, Kuehl W M, Eckhardt L A
Department of Biological Sciences, Columbia University, New York, New York 10027.
J Immunol. 1993 Sep 1;151(5):2588-600.
It has been well-established that Ig genes are transcriptionally silenced when Ig-producing myeloma lines are fused to non-B cells. In the present study, we analyzed the expression of several other myeloma-specific genes in fusions of myelomas with the T lymphoma, BW5147. Seven of the eight genes analyzed behaved coordinately with the Ig loci; they were silent in most myeloma x T hybrids but active in the rare hybrid that retained Ig gene expression. Cloned IgH genes introduced into the two types of hybrids behaved as their endogenous counterparts. The coordinate behavior of these several genes in the panel of "exceptional" and "extinguished" hybrids suggests a central and bimodal switch for alternately activating and de-activating the genetic program of the Ig-secreting plasmacyte. The switch between an active and an inactive transcriptional state involves, at some level, a change in the methylation status of the IgH genes. Methylation and transcriptional activity were inversely correlated. In Ig-extinguished hybrids the myeloma-derived locus was methylated de novo, whereas in the rare Ig-expressing hybrid, the T cell-derived locus was demethylated de novo.
已经充分证实，当产生免疫球蛋白（Ig）的骨髓瘤细胞系与非B细胞融合时，Ig基因会发生转录沉默。在本研究中，我们分析了骨髓瘤与T淋巴瘤BW5147融合体中其他几个骨髓瘤特异性基因的表达情况。所分析的八个基因中有七个与Ig基因座协同作用；它们在大多数骨髓瘤×T杂交细胞中沉默，但在罕见的保留Ig基因表达的杂交细胞中活跃。导入这两种杂交细胞中的克隆IgH基因表现与其内源性对应物相同。这些基因在“特殊”和“沉默”杂交细胞组中的协同行为表明，存在一个核心的双峰开关，用于交替激活和失活分泌Ig的浆细胞的遗传程序。活跃和非活跃转录状态之间的转换在某种程度上涉及IgH基因甲基化状态的改变。甲基化与转录活性呈负相关。在Ig沉默的杂交细胞中，骨髓瘤来源的基因座会重新发生甲基化，而在罕见的表达Ig的杂交细胞中，T细胞来源的基因座会重新发生去甲基化。
