Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma.
The oncogene c-maf is translocated in approximately 5%-10% of multiple myelomas. Unexpectedly, we observed c-maf expression in myeloma cell lines lacking c-maf translocations and in 50% of multiple myeloma bone marrow samples. By gene expression profiling, we identified three c-maf target genes: cyclin D2, integrin beta7, and CCR1. c-maf transactivated the cyclin D2 promoter and enhanced myeloma proliferation, whereas dominant inhibition of c-maf blocked tumor formation in immunodeficient mice. c-maf-driven expression of integrin beta7 enhanced myeloma adhesion to bone marrow stroma and increased production of VEGF. We propose that c-maf transforms plasma cells by stimulating cell cycle progression and by altering bone marrow stromal interactions. The frequent overexpression of c-maf in myeloma makes it an attractive target for therapeutic intervention.
Hurt
Elaine M
EM
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Wiestner
Adrian
A
Rosenwald
Andreas
A
Shaffer
A L
AL
Campo
Elias
E
Grogan
Tom
T
Bergsagel
P Leif
PL
Kuehl
W Michael
WM
Staudt
Louis M
LM
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000503:physiopathology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D009101:Multiple Myeloma / Q000378:metabolism* / Q000503:physiopathology; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051257:Proto-Oncogene Proteins c-maf; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D014183:Transplantation, Heterologous / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C080336:CCND2 protein, human; D015820:Cadherins; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D004268:DNA-Binding Proteins; D039641:Integrin beta Chains; C495607:MAF protein, human; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D042461:Vascular Endothelial Growth Factor A; C091368:integrin beta7; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases