Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Blood. 2011 Jan 6;117(1):211-20. doi: 10.1182/blood-2010-07-298349. Epub 2010 Oct 25.
The multiple myeloma SET domain (MMSET) protein is overexpressed in multiple myeloma (MM) patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/Wolf-Hirschhorn syndrome candidate 1 in development, its mode of action in the pathogenesis of MM is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth, and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation, and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM.
多发性骨髓瘤 SET 结构域（MMSET）蛋白在伴有 t（4；14）易位的多发性骨髓瘤（MM）患者中过度表达。尽管研究表明 MMSET/Wolf-Hirschhorn 综合征候选基因 1 参与了疾病的发展，但它在 MM 发病机制中的作用方式在很大程度上尚不清楚。我们发现 MMSET 是 t（4；14）MM 细胞中染色质结构和转录的主要调节剂。高水平的 MMSET 与组蛋白 H3 赖氨酸 36 甲基化增加和整个基因组赖氨酸 27 甲基化减少相关，导致染色质结构更开放。MMSET 表达的缺失改变了 MM 细胞的黏附特性，抑制了生长，并诱导了细胞凋亡。因此，受高水平 MMSET 影响的基因与 p53 途径、细胞周期调控和整合素信号转导有关。许多这些基因的调控需要 MMSET 的功能性组蛋白甲基转移酶活性。这些结果表明 MMSET 是 t（4；14）+ MM 中的主要表观遗传调节剂。
