Brito Jose L R, Walker Brian, Jenner Matthew, Dickens Nicholas J, Brown Nicola J M, Ross Fiona M, Avramidou Athanasia, Irving Julie A E, Gonzalez David, Davies Faith E, Morgan Gareth J
Institute for Cancer Research, Section of Haemato-Oncology, London, UK.
Haematologica. 2009 Jan;94(1):78-86. doi: 10.3324/haematol.13426. Epub 2008 Dec 4.
The recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is associated with poor prognosis, through an unknown mechanism. The t(4;14) up-regulates fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET) genes. The involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear.
The expression of MMSET was analyzed using a novel antibody. The involvement of MMSET in t(4;14) myelomagenesis was assessed by small interfering RNA mediated knockdown combined with several biological assays. In addition, the differential gene expression of MMSET-induced knockdown was analyzed with expression microarrays. MMSET gene targets in primary patient material was analyzed by expression microarrays.
We found that MMSET isoforms are expressed in multiple myeloma cell lines, being exclusively up-regulated in t(4;14)-positive cells. Suppression of MMSET expression affected cell proliferation by both decreasing cell viability and cell cycle progression of cells with the t(4;14) translocation. These findings were associated with reduced expression of genes involved in the regulation of cell cycle progression (e.g. CCND2, CCNG1, BRCA1, AURKA and CHEK1), apoptosis (CASP1, CASP4 and FOXO3A) and cell adhesion (ADAM9 and DSG2). Furthermore, we identified genes involved in the latter processes that were differentially expressed in t(4;14) multiple myeloma patient samples.
In conclusion, dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival.
复发性免疫球蛋白易位，t(4;14)(p16;q32)发生于15%的多发性骨髓瘤患者中，通过未知机制与不良预后相关。t(4;14)上调成纤维细胞生长因子受体3（FGFR3）和多发性骨髓瘤SET结构域（MMSET）基因。MMSET在t(4;14)多发性骨髓瘤发病机制中的作用以及MMSET上调所导致的失调机制或基因仍不清楚。
使用一种新型抗体分析MMSET的表达。通过小干扰RNA介导的敲低结合多种生物学检测评估MMSET在t(4;14)骨髓瘤发生中的作用。此外，用表达微阵列分析MMSET诱导敲低后的差异基因表达。通过表达微阵列分析原发性患者材料中的MMSET基因靶点。
我们发现MMSET异构体在多发性骨髓瘤细胞系中表达，仅在t(4;14)阳性细胞中上调。抑制MMSET表达通过降低t(4;14)易位细胞的细胞活力和细胞周期进程来影响细胞增殖。这些发现与参与细胞周期进程调控（如CCND2、CCNG1、BRCA1、AURKA和CHEK1）、细胞凋亡（CASP1、CASP4和FOXO3A）以及细胞黏附（ADAM9和DSG2）的基因表达降低有关。此外，我们鉴定出了在t(4;14)多发性骨髓瘤患者样本中差异表达的参与后述过程的基因。
总之，MMSET失调影响了参与细胞周期进程、细胞黏附和存活调控的多个基因的表达。
