Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia.

Begüm Alankus,Wilko Weichert,Nathalie Vahl,Martina Braun,Maike Buchner,Torben Gehring,Tanja Neumayer,Jürgen Ruland,Stephan Macher-Göppinger,Veronika Ecker,Thorsten Zenz

doi:10.1084/jem.20200517

Abstract

Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell-intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma-derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus-like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL-RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell-intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment.

Highlights

B lymphocytes are critical for adaptive immunity and host syndrome
RANKK240E expression induces ligand-dependent B cell activation with B1 cell expansion To study pathological RANK signaling in B cells in vivo, we first explored whether the human lymphoma–derived RANKK240E variant (Davis et al, 2010) could be used as a tool in murine cells
The expanded B cells were of polyclonal origin (Fig. 3 E) and showed a two- to threefold increase in the mutation frequency of their variable heavy (VH) region compared with littermate control B cells, indicating that they had undergone somatic hypermutations (SHMs; Fig. 3 F)

Summary

Introduction

B lymphocytes are critical for adaptive immunity and host syndrome (reviewed in Goodnow, 2007). Large protection against infection (LeBien and Tedder, 2008), but epidemiological studies have demonstrated an increased inciwhen dysregulated they can drive autoimmunity or develop dence of B cell malignancies in patients with such autoimmune into malignant lymphomas (Goodnow, 2007; Kwak et al, 2019; conditions (Bernatsky et al, 2006).

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