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

Elaine M Hurt; Adrian Wiestner; Andreas Rosenwald; A L Shaffer; Elias Campo; Tom Grogan; P Leif Bergsagel; W Michael Kuehl; Louis M Staudt

doi:10.1016/s1535-6108(04)00019-4

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.

Authors

Elaine M Hurt¹, Adrian Wiestner, Andreas Rosenwald, A L Shaffer, Elias Campo, Tom Grogan, P Leif Bergsagel, W Michael Kuehl, Louis M Staudt

Affiliation

¹ Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

PMID: 14998494
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