Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma.
OBJECTIVE
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.


METHODS
Nine HMCL were characterized by fluorescent in situ hybridization, comparative genomic hybridization (CGH) and cDNA microarrays for gene expression profiling and copy number changes.


RESULTS
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.


CONCLUSIONS
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.
Largo
Cristina
C
Cytogenetics Unit, Spanish National Cancer Centre, (CNIO), C/ Melchor Fernandez Almagro 3, Madrid, 28029, Spain.
Alvarez
Sara
S
Saez
Borja
B
Blesa
David
D
Martin-Subero
Jose I
JI
González-García
Ines
I
Brieva
Jose A
JA
Dopazo
Joaquin
J
Siebert
Reiner
R
Calasanz
María J
MJ
Cigudosa
Juan C
JC
D020169:Caspases; D045744:Cell Line, Tumor; D002877:Chromosomes, Human; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D052138:Genes, Neoplasm; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009101:Multiple Myeloma / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics
D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein