Identification of genes modulated in multiple myeloma using genetically identical twin samples
Identification of genes modulated in multiple myeloma using genetically identical twin samples
复制标题
DOI：
10.1182/blood-2003-02-0402
复制
发表时间：
2004-03-01
期刊：
影响因子：
20.3
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Munshi, NC;Hideshima, T;Anderson, KC
个体之间的遗传异质性混淆了多发性骨髓瘤（MM）细胞与正常浆细胞（PC）基因谱的比较。为了克服这一障碍，我们使用微阵列分析比较了来自患者骨髓（BM）样本的CD 138（+）MM细胞与来自遗传上相同的双胞胎BM样本的CD 138（+）PC的基因表达谱。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细胞中的高表达基因包括细胞存活途径基因（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、钙连接蛋白和FGFR-3）、应激反应和泛素/蛋白酶体途径相关基因以及反映代谢和翻译活性增加的各种核糖体基因。与健康双胞胎PC相比，MM细胞中下调的基因包括RAD 51、杀伤细胞免疫球蛋白样受体蛋白和凋亡蛋白酶激活因子。芯片结果进一步证实了Western印迹分析，免疫组化，荧光原位杂交（FISH），端粒酶活性和骨髓血管生成的功能测定。这种分子分析提供了潜在的见解恶性转化的机制在MM。例如，FGFR 3，xbp-1，和mcl-1和爸爸-1可能介导的转化，分化和生存，分别，并可能具有临床意义。通过鉴定MM细胞中与相同基因型背景下的正常PC相比发生独特改变的基因，目前的研究提供了鉴定新治疗靶点的框架。(C)2004年，美国血液学会。
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 anglogenesis. 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. (C) 2004 by The American Society of Hematology.