Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma

Cancer Cell. 2004 Feb;5(2):191-9. doi: 10.1016/s1535-6108(04)00019-4.

Abstract

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.

MeSH terms

  • Animals
  • Bone Marrow / metabolism*
  • Bone Marrow / physiopathology
  • Cadherins / metabolism
  • Cell Adhesion / physiology
  • Cyclin D2
  • Cyclins / metabolism
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Profiling
  • Humans
  • Integrin beta Chains / metabolism
  • Mice
  • Models, Animal
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / physiopathology
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Plasma Cells / cytology
  • Plasma Cells / metabolism*
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-maf
  • Stromal Cells / cytology
  • Stromal Cells / metabolism*
  • Transplantation, Heterologous / pathology
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • CCND2 protein, human
  • Cadherins
  • Ccnd2 protein, mouse
  • Cyclin D2
  • Cyclins
  • DNA-Binding Proteins
  • Integrin beta Chains
  • MAF protein, human
  • Maf protein, mouse
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-maf
  • Vascular Endothelial Growth Factor A
  • integrin beta7
  • SNF1-related protein kinases
  • Protein-Serine-Threonine Kinases