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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1799-1806.
Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-02-0402.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Identification of genes modulated in multiple myeloma using genetically identical twin samples
Nikhil C. Munshi,
Teru Hideshima,
Daniel Carrasco,
Masood Shammas,
Daniel Auclair,
Faith Davies,
Nicholas Mitsiades,
Constantine Mitsiades,
Ryung Suk Kim,
Cheng Li,
S. Vincent Rajkumar,
Rafael Fonseca,
Lief Bergsagel,
Dharminder Chauhan, and
Kenneth C. Anderson
From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and the Boston VA Healthcare System, Harvard Medical School, the Harvard School of Public Health, Boston, MA; the University of Leeds, United Kingdom; the Mayo Clinic Medical Center, Rochester, MN; and the Weil College of Cornell University, New York, NY.
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.
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