Congenital B cell lymphocytosis explained by novel germline CARD11 mutations.

Snow AL, Xiao W, Stinson JR, Lu W, Chaigne-Delalande B, Zheng L, Pittaluga S, Matthews HF, Schmitz R, Jhavar S, Kuchen S, Kardava L, Wang W, Lamborn IT, Jing H, Raffeld M, Moir S, Fleisher TA, Staudt LM, Su HC, Lenardo MJ.
Source: J Exp Med
Publication Date: (2012)
Issue: 209(12): 2247-2261
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Gene Expression
Cells used in publication:
B cell, human
Species: human
Tissue Origin: blood
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
4D-Nucleofector® X-Unit
5µg DNA using an Amaxa 4D Nucleofector (kit SE, Program CL-120; Lonza). BJAB cells (5 × 106/transfection) were transfected with 5 µg DNA using an Amaxa 4D Nucleofector (kit SF, Program EH-100). Primary human T cells were transfected with 4 mg DNA using an Amaxa 4D Nucleofector (kit P3, HF program for unstimulated T cells).
Nuclear factor-?B (NF-?B) controls genes involved in normal lymphocyte functions, but constitutive NF-?B activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)-induced NF-?B activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-?B activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.