Munshi Nikhil C, Hideshima Teru, Carrasco Daniel, Shammas Masood, Auclair Daniel, Davies Faith, Mitsiades Nicholas, Mitsiades Constantine, Kim Ryung Suk, Li Cheng, Rajkumar S Vincent, Fonseca Rafael, Bergsagel Lief, Chauhan Dharminder, Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston MA 02115, USA.
Blood. 2004 Mar 1;103(5):1799-806. doi: 10.1182/blood-2003-02-0402. Epub 2003 Sep 11.
Genetic heterogeneity between individuals confounds the comparison of gene profiling of multiple myeloma (MM) cells versus normal plasma cells (PCs). To overcome this barrier, we compared the gene expression profile of CD138+ MM cells from a patient bone marrow (BM) sample with CD138+ PCs from a genetically identical twin BM sample using microarray profiling. Two hundred and ninety-six genes were up-regulated and 103 genes were down-regulated at least 2-fold in MM cells versus normal twin PCs. Highly expressed genes in MM cells included cell survival pathway genes such as mcl-1, dad-1, caspase 8, and FADD-like apoptosis regulator (FLIP); oncogenes/transcriptional factors such as Jun-D, Xbp-1, calmodulin, Calnexin, and FGFR-3; stress response and ubiquitin/proteasome pathway-related genes and various ribosomal genes reflecting increased metabolic and translational activity. Genes that were down-regulated in MM cells versus healthy twin PCs included RAD51, killer cell immunoglobulin-like receptor protein, and apoptotic protease activating factor. Microarray results were further confirmed by Western blot analyses, immunohistochemistry, fluorescent in situ hybridization (FISH), and functional assays of telomerase activity and bone marrow angiogenesis. This molecular profiling provides potential insights into mechanisms of malignant transformation in MM. For example, FGFR3, xbp-1, and both mcl-1 and dad-1 may mediate transformation, differentiation, and survival, respectively, and may have clinical implications. By identifying genes uniquely altered in MM cells compared with normal PCs in an identical genotypic background, the current study provides the framework to identify novel therapeutic targets.
个体之间的基因异质性使得多发性骨髓瘤（MM）细胞与正常浆细胞（PC）的基因谱比较变得复杂。为了克服这一障碍，我们使用微阵列分析，将来自患者骨髓（BM）样本的CD138+ MM细胞的基因表达谱与来自基因相同的双胞胎BM样本的CD138+ PC的基因表达谱进行了比较。与正常双胞胎PC相比，MM细胞中有296个基因上调，103个基因下调至少2倍。MM细胞中高表达的基因包括细胞存活通路基因，如mcl-1、dad-1、半胱天冬酶8和FADD样凋亡调节因子（FLIP）；癌基因/转录因子，如Jun-D、Xbp-1、钙调蛋白、钙连蛋白和FGFR-3；应激反应和泛素/蛋白酶体途径相关基因以及各种反映代谢和翻译活性增加的核糖体基因。与健康双胞胎PC相比，MM细胞中下调的基因包括RAD51、杀伤细胞免疫球蛋白样受体蛋白和凋亡蛋白酶激活因子。微阵列结果通过蛋白质印迹分析、免疫组织化学、荧光原位杂交（FISH）以及端粒酶活性和骨髓血管生成的功能测定得到进一步证实。这种分子谱分析为MM恶性转化机制提供了潜在的见解。例如，FGFR3、xbp-1以及mcl-1和dad-1可能分别介导转化、分化和存活，并且可能具有临床意义。通过在相同基因型背景下识别与正常PC相比在MM细胞中独特改变的基因，本研究为识别新的治疗靶点提供了框架。
