TY - JOUR
T1 - Congenital B cell lymphocytosis explained by novel germline CARD11 mutations
AU - Snow, Andrew L.
AU - Xiao, Wenming
AU - Stinson, Jeffrey R.
AU - Lu, Wei
AU - Benjamin, Chaigne Delalande
AU - Zheng, Lixin
AU - Pittaluga, Stefania
AU - Matthews, Helen F.
AU - Schmitz, Roland
AU - Jhavar, Sameer
AU - Kuchen, Stefan
AU - Kardava, Lela
AU - Wang, Wei
AU - Lamborn, Ian T.
AU - Jing, Huie
AU - Raffeld, Mark
AU - Moir, Susan
AU - Fleisher, Thomas A.
AU - Staudt, Louis M.
AU - Su, Helen C.
AU - Lenardo, Michael J.
PY - 2012/11
Y1 - 2012/11
N2 - Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions,but constitutive NF-κB 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-κB 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-κB 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 induceB cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.
AB - Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions,but constitutive NF-κB 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-κB 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-κB 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 induceB cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.
UR - http://www.scopus.com/inward/record.url?scp=84870784256&partnerID=8YFLogxK
U2 - 10.1084/jem.20120831
DO - 10.1084/jem.20120831
M3 - Article
C2 - 23129749
AN - SCOPUS:84870784256
SN - 0022-1007
VL - 209
SP - 2247
EP - 2261
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -