Figure 8
Differential dependence on – and expression of – pro-survival BCL-2 family members throughout B-cell development. (a) Dependence on expression of MCL-1, BCL-2 and BCL-XL throughout B-cell development. Solid lines indicate direct reliance on indicated BCL-2 family protein based on both in vivo data and ex vivo experiments using BH3-mimetics, whereas dotted lines indicate reliance on either in vivo data or ex vivo experiments with BH3-mimetics. Data are a summary of Figures 1c,2a,4a, 4c, 4d,6a and 7. (b) Regulation of Mcl1, Bcl2, Bclx (Bcl2l1) and A1 (Bcl2a1) gene expression in germinal center (GC) B cells and PC. BCL-6-mediated inhibition of PC master regulator Blimp-1 can be abrogated by activation of IRF4.33 This can be achieved by NF-κB activation following CD40 ligation.34 Activated NF-κB can promote transcription of pro-survival BCL-2 family protein A1 (BFL-1),35 which is subsequently inhibited by Blimp-1 when cells differentiate to PC.16 Blimp-1 can promote transcription of Bclx, which is subsequently repressed by XBP-1.30, 31 Expression of Mcl1 is transcriptionally induced by stimulation of BCMA in the BM microenvironment,16 however, the mechanism of increased Mcl1 transcription in splenic PC remains unclear. Repression of Bcl2 has been observed in the early GC but is subsequently re-expressed in mature PC,16 although the upstream mediators are currently unknown
