Congenital B cell lymphocytosis linked to a novel germline CARD11 mutation (109.13)

Abstract

Abstract Nuclear Factor-kappa B (NF-κB) governs the transcription of many genes for normal lymphocyte functions, but constitutive NF-κB activation is most often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we recently investigated a family with a unique, hereditary polyclonal B cell lymphocytosis. Here we report our discovery of a novel, germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a lymphocyte-specific scaffolding protein required for antigen receptor (AgR)-induced NF-κB activation in both B and T lymphocytes. Similar to somatic, gain-of-function CARD11 mutations described in diffuse large B cell lymphoma, E127G CARD11 spontaneously oligomerizes and activates NF-κB when upon ectopic expression in lymphoid cell lines. Primary lymphocytes from these patients also display evidence of CARD11 aggregation and constitutive NF-κB activity. In contrast to B cells, however, we observed that E127G CARD11 contributes to patient T cell hyporesponsiveness upon AgR stimulation, even though the proximal CARD11-associated signaling machinery is highly similar between B and T cells. Our findings suggest that an activating, germline CARD11 mutation can selectively induce B cell expansion and preferentially predispose to B cell malignancy without perturbing T cell homeostasis.