Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice

Abstract

Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the BAFF receptor (BAFF-R), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v-AKT murine thymoma viral oncogene homolog 1 (AKT)/PI3-kinase network, BAFF/BAFF-R-mediated survival engages non-canonical NF-κB signaling as well as MAPK/extracellular-signal regulated kinase and AKT/PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of BAFF-R and regulated by APRIL that signals NF-κB activation via alternative receptors, that is, transmembrane activator and CAML interactor (TACI) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic B-cell lymphoma 2 (Bcl2) family proteins in developing and mature B cells. Curiously, how lack of BAFF- or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the ‘Bcl2 homology domain 3-only' subgroup of the Bcl2 family, Bcl2 interacting mediator of cell death (Bim) and Bcl2 modifying factor (Bmf), mediate apoptosis in the context of TACI-Ig overexpression that effectively neutralizes BAFF as well as APRIL. Surprisingly, although Bcl2 overexpression triggers B-cell hyperplasia exceeding the one observed in Bim−/−Bmf−/− mice, Bcl2 transgenic B cells remain susceptible to the effects of TACI-Ig expression in vivo, leading to ameliorated pathology in Vav-Bcl2 transgenic mice. Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that Bcl2 antagonists might improve the potency of BAFF/APRIL-depletion strategies in B-cell-driven pathologies.

Transient apoptosis inhibition in donor stem cells improves hematopoietic stem cell transplantation

“…These data suggested that inhibition of BIM and/or BMF in donor HSPCs could be a useful means to achieve superior transplantation outcome. Permanent apoptosis resistance, however, is associated with an increased risk of leukemogenesis and autoimmunity, and recipient mice transplanted with Bim −/− or Bim −/− Bmf −/− BM cells died of autoimmune kidney disease and/or lymphoma within 1 yr ( Labi et al, 2014 ; Woess et al, 2015 ).…”

Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat

“…S6C). In all these conditions, loss of BIM had been reported to exert anti-apoptotic activity (Oliver et al 2006;Woess et al 2015 Figure 6. Specific disruption of miR-17∼92:Bim interactions does not detectably affect B cells.…”

Application of mid-infrared (MIR) microscopy imaging for discrimination between follicular hyperplasia and follicular lymphoma in transgenic mice

“…Histological evaluation of spleens from double-transgenic mice indicated reduced follicle and germinal center size. 6…”