Identification of primary MAFB target genes in multiple myeloma.
OBJECTIVE
In multiple myeloma (MM), seven primary recurrent translocations involving the immunoglobulin heavy chain locus have been identified. One of the partner loci maps to 20q12 and involves the MAFB gene resulting in its ectopic expression. We attempt here to identify MAFB target genes in MM.


METHODS
We used an inducible system to upregulate MAFB in MM cell lines not carrying the t(14;20). Microarray expression analysis was used to detect gene expression changes upon MAFB expression. These genes were further evaluated comparatively with gene expression profiles obtained from MM or plasma cell leukemia tumors carrying an activated MAFB gene. Functional implications of these upregulated genes were studied by testing their promoter activity in reporter assays. C-MAF was included comparatively as well.


RESULTS
The inducible cell lines identified a total of 284 modulated transcripts. After further evaluation using ex vivo data 14 common upregulated genes were found, common to the C-MAF pathway as well. The promoter activity of some of these secondary genes proved a functional relationship with MAFB. In connection with one of these secondary genes (NOTCH2), even tertiary upregulated genes were found. Functional studies indicated that inducible MAFB expression conferred antiapoptotic effects.


CONCLUSIONS
We identified 14 upregulated genes, and their downstream consequences in the combined MAFB/C-MAF pathway. Eleven of these genes are novel in the C-MAF pathway as well. These direct target genes may be responsible for the oncogenic transformation of MAF expressing myeloma cells.
van Stralen
Esther
E
University Medical Center Utrecht, Department of Immunology, Utrecht, The Netherlands; Hubrecht Laboratory, Center for Biomedical Genetics, Utrecht, The Netherlands.
van de Wetering
Marc
M
Agnelli
Luca
L
Neri
Antonino
A
Clevers
Hans C
HC
Bast
Bert J E G
BJ
D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D051258:MafB Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics
D007143:Immunoglobulin Heavy Chains; C495607:MAF protein, human; C490407:MAFB protein, human; D051258:MafB Transcription Factor; D051257:Proto-Oncogene Proteins c-maf