FOXP1 directly represses transcription of pro-apoptotic genes and cooperates with NF-κB to promote survival of human B-cells

Martine van Keimpema, Leonie J. Grüneberg, Michal Mokry, Ruben van Boxtel, Jan Koster, Paul J. Coffer, Steven T. Pals and Marcel Spaargaren

Key points

  • FOXP1 directly represses multiple pro-apoptotic genes in primary mature human B-cells and DLBCL cell lines.

  • FOXP1 cooperates with NF-κB signaling to promote expansion of primary mature human B-cells, by inhibition of caspase-dependent apoptosis.


The forkhead transcription factor FOXP1 is involved in B-cell development and function, and is generally regarded as an oncogene in activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma, lymphomas relying on constitutive NF-κB activity for survival. However, the mechanism underlying its putative oncogenic activity has not been established. By gene expression microarray, upon overexpression or silencing of FOXP1 in primary human B-cells and DLBCL cell-lines, combined with chromatin-immunoprecipitation followed by next-generation sequencing (ChIP-seq), we established that FOXP1 directly represses a set of 7 pro-apoptotic genes. Low expression of these genes, encoding the BH3-only proteins BIK and Harakiri, the p53-regulatory proteins TP63, RASSF6 and TP53INP1, AIM2 and EAF2, is associated with poor survival in DLBCL patients. In line with these findings, we demonstrated that FOXP1 promotes the expansion of primary mature human B-cells by inhibiting caspase-dependent apoptosis, without affecting B-cell proliferation. Furthermore, FOXP1 is dependent upon, and cooperates with, NF-κB signaling to promote B-cell expansion and survival. Taken together, our data indicate that, through direct repression of pro-apoptotic genes, (aberrant) expression of FOXP1 complements (constitutive) NF-κB activity to promote B-cell survival, and can thereby contribute to B-cell homeostasis and lymphomagenesis.

  • Submitted January 30, 2014.
  • Accepted September 8, 2014.