Largo Cristina, Alvarez Sara, Saez Borja, Blesa David, Martin-Subero Jose I, González-García Ines, Brieva Jose A, Dopazo Joaquin, Siebert Reiner, Calasanz María J, Cigudosa Juan C
Cytogenetics Unit, Spanish National Cancer Centre, (CNIO), C/ Melchor Fernandez Almagro 3, Madrid, 28029, Spain.
Haematologica. 2006 Feb;91(2):184-91.
Multiple myeloma (MM) is a malignancy characterized by clonal expansion of plasma cells. In 50% of the cases, the neoplastic transformation begins with a chromosomal translocation that juxtaposes the IGH gene locus to an oncogene. Gene copy number changes are also frequent in MM but less characterized than in other neoplasias. We aimed to characterize genes that are amplified and overexpressed in human myeloma cell lines (HMCL) to provide putative molecular targets for MM therapy.
Nine HMCL were characterized by fluorescent in situ hybridization, comparative genomic hybridization (CGH) and cDNA microarrays for gene expression profiling and copy number changes.
After defining the IGH-translocations present in the cell lines, we conducted expression-profiling analysis. Supervised analysis identified 166 genes with significantly different expression among the cell lines harboring MMSET/FGFR3 (4p16), MAF (16q) and CCND1 (11q13) rearrangements. Array-CGH was then performed. Five chromosomes recurrently affected by gains/amplifications in primary samples and cell lines were analyzed in detail. Sixty amplified and overexpressed genes were found and 25 (42%) of them were only overexpressed when amplified; moreover, six showed a significant association between overexpression and gain/amplification. We also found co-amplification and overexpression for genes located within the same amplicons, such as MALT1 and BCL2.
Parallel analysis of gene copy numbers and expression levels by cDNA microarray in MM allowed efficient identification of genes whose expression levels are elevated because of increased copy number. This is the first time that MALT1 and BCL2 have been shown to be overexpressed and amplified in MM.
多发性骨髓瘤（MM）是一种以浆细胞克隆性增殖为特征的恶性肿瘤。在50%的病例中，肿瘤转化始于染色体易位，该易位使IGH基因座与一个癌基因并列。基因拷贝数变化在MM中也很常见，但与其他肿瘤相比，其特征描述较少。我们旨在鉴定在人骨髓瘤细胞系（HMCL）中扩增并过表达的基因，为MM治疗提供潜在的分子靶点。
通过荧光原位杂交、比较基因组杂交（CGH）和cDNA微阵列对9个HMCL进行基因表达谱分析和拷贝数变化分析。
在确定细胞系中存在的IGH易位后，我们进行了表达谱分析。监督分析确定了166个基因，这些基因在携带MMSET/FGFR3（4p16）、MAF（16q）和CCND1（11q13）重排的细胞系中表达存在显著差异。然后进行了阵列CGH分析。详细分析了在原发性样本和细胞系中反复受增益/扩增影响的5条染色体。发现了60个扩增并过表达的基因，其中25个（42%）仅在扩增时过表达；此外，6个基因的过表达与增益/扩增之间存在显著关联。我们还发现了位于同一扩增子内的基因，如MALT1和BCL2的共扩增和过表达。
通过cDNA微阵列对MM中的基因拷贝数和表达水平进行平行分析，能够有效地鉴定出因拷贝数增加而表达水平升高的基因。这是首次证明MALT1和BCL2在MM中过表达并扩增。
