The role of transcription factor MAFB in Multiple Myeloma

Abstract

The starting point of this study was the description by our group of a novel chromosomal translocation in cell lines, obtained from Multiple Myeloma (MM) patients, i.e. the t(14;20)(q32;q12) 1. Subsequent work is reported in this thesis. In summary, we have shown in chapter 2 that as a result of this t(14;20) the transcription factor MAFB is up regulated. In addition we have shown that the t(14;20) is a primary translocation indeed. In chapter 3 we describe the primary target genes that are up regulated by MAFB over expression in vitro and in primary patient BM samples. We found even secondary target genes and identified the Notch pathway as an important result caused by MAFB over expression. Furthermore, we show that the target genes found by over expression of MAFB also are up regulated by C-MAF over expression, suggesting that members of the large Maf group activate the same pathways in MM development. In chapter 4 we describe a new generated anti-MAFB monoclonal antibody. By using this antibody for staining BM biopsies by IHC, MAFB oncoprotein expression was detected in patients carrying t(14;20), but only there. Therefore this MoAb may be used as a prognostic marker in risk stratification of MM, and it may be used to detect minimal residual disease (MRD) as well. To study MM development in vivo we generated a MAFB transgenic mouse, which results are described in Chapter 5. Human MAFB cDNA was placed under the control of the human CD19 promoter and a duplicate of the mouse E? enhancer. With this combination, high levels of MAFB expression were expected in the whole B-cell lineage but mainly in the late B-cell development. Higher IgM levels were detected in E?-CD19-MAFB transgenic mice compared to wild-type mice. However, after a year of monitoring the E?-CD19-MAFB transgenic mice, but no aberrant B-cell development or a MM phenotype was observed yet.