Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells

Abstract

SignificanceMany patients with B cell lymphoma carry alterations in the gene coding for the transcription factor Foxp1. High Foxp1 expression has been linked to poor prognosis in those malignancies; however, the physiological functions of Foxp1 in mature B cells remain unknown. By employing genetic mouse models, we show that Foxp1 deletion results in reduced B cell numbers and impaired antibody production upon T cell-independent immunization. Foxp1-deficient mature B cells are impaired in survival and exhibit an increased proliferation capacity, and transcriptional analysis identified defective expression of the prosurvival Bcl-xl gene. Our results provide insight into the regulation of mature B cell survival by Foxp1 and have implications for understanding the role of Foxp1 in the development of B cell malignancies.

Loss of the FOXP1 Transcription Factor Leads to Deregulation of B Lymphocyte Development and Function at Multiple Stages

“…However, we observed defects in both T-independent and -dependent immunization, which we traced to faulty CSR and GC formation. Finally, both in this study and previously in human DLBCL (23), we confirmed the observation of Patzelt et al (95) of defective expression of prosurvival BCL-2 family members, some of which we showed by ChIP-seq to be direct in human cell lines. In addition to survival, our RNA-seq, GSEA, and ChIP-seq analyses revealed critical FOXP1 target genes regulating GC biology, CSR, PB-to-PC transition, and cytokine production.…”

“…However, by employing T1 stage deletion with Cd21-cre, we were able to bypass the pro-B cell block (which led to loss of FO B cells in the periphery and peritoneal cavities) to identify an additional, significant reduction in Bregs. As with Patzelt et al (95), we found Foxp1-deficient B cells to be impaired in survival without significant consequence on proliferation (particularly following stimulation with anti-IgM). However, we observed defects in both T-independent and -dependent immunization, which we traced to faulty CSR and GC formation.…”

“…During the preparation of this manuscript, Patzelt et al (95) employed Cd19-cre-mediated deletion to address the function of Foxp1 in mature B cells. By employing both Cd19-and mb1-cre approaches, we confirmed their finding that Foxp1 loss resulted in significant reduction in mature FO B cells, but in MZB cells.…”

Loss of TRP53 (p53) accelerates tumorigenesis and changes the tumor spectrum of SJL/J mice

“…In fact, Foxp1 directly represses p53-dependent regulatory proteins in neoplastic B-cells, suggesting a strong role in immune modulation [56]. As we currently understand normal anti-cancer responses, a functional immune system is a key component that suppresses cancer [57][58][59]: Foxp1 controls mature B-cell survival and development, and is a regulator for CD4+ T cells [60,61]. Thus, it is also likely that Foxp1 is an essential component that controls the lymphoid immune system, and thereby a modulator of tumorigenesis.…”

Building gene regulatory networks from scATAC-seq and scRNA-seq using Linked Self-Organizing Maps

“…2e). Similarly, metacluster 25 consists of 33 units and contains 151 genes enriched in 24-hour cells such as Mier1 and Foxp1, which has been shown to control mature B-cell survival in mice 26 (Fig. 2e).…”