Consequences of oncogenic CARD11 signalling for B cells
Date
2015
Authors
Jeelall, Yogesh
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Abstract
Diffuse large B cell lymphoma is the most common form of Non
Hodgkin’s lymphoma, accounting for forty percent of cases.
Gain of function CARD11 mutations have been found in
approximately thirteen percent of DLBCL patients. CARD11
functions as a scaffold protein and relays signals from the
antigen receptor to the JNK and NFkB signaling pathways, which
contribute to the survival, proliferation and differentiation of
lymphocytes. The consequences of acquiring gain of function
CARD11 mutations in normal B lymphocytes, in isolation from the
other approximately 30 mutations that accumulate on average in
lymphoma cells, had not been previously addressed. By introducing
lymphoma CARD11 mutations into antigen activated B lymphocytes,
we found that gain of function CARD11 mutations result in
proliferation, growth and survival in vitro. The CARD11 mutants
also increased signalling to NFkB and JNK pathways to varying
degrees.
Moreover, when the genetically modified B cells were transferred
in vivo to investigate the consequences of the acquisition of the
CARD11Mut10 version of CARD11, we observed that the B cells
proliferate rapidly and differentiate into plasmablasts.
CARD11Mut10 induced BLIMP1 mediated plasmablast differentiation
and autocrine production of IL6, which contributed to
differentiation into plasmablasts. However, this initial rapid
population expansion was self-limiting: it peaked at day 10, and
by 20 days the numbers of CARD11Mut10 expressing B cells
decreased drastically. The induction of the NFkB negative
regulator A20 contributed to limiting the expansion and
accumulation of CARD11Mut10 expressing B cells.
By introducing CARD11 mutations from human lymphomas into antigen
activated mature B lymphocytes in mice, we tested the hypothesis
that lymphoma somatic mutations corrupt the normal response to
self-antigens. Here, we show that all lymphoma derived CARD11
mutations tested, but not NFkB activating mutations in Ikbkb,
block self-antigen induced death and cooperate with chronic
antigen receptor stimulation to induce extensive T cell
independent proliferation, BLIMP1 mediated plasmablast
differentiation and autoantibody secretion. Our findings
demonstrate that regulation of CARD11 signalling is a critical
switch governing the decision between death and proliferation in
antigen-stimulated mature B cells, and that mutations in this
switch represent a powerful initiator for aberrant B cell
responses in vivo.
Recently, patients with germline activating mutations in CARD11
were reported. These patients are characterised by a B cell
lymphoproliferative disorder, with B cell expansion with NFkB and
T cell anergy. We show that E127G CARD11, discovered in patients
with germline CARD11 mutations, increased NFkB signalling and,
akin to lymphoma derived CARD11 mutants, E127G CARD11 protected
the B cells from death and induced accumulation of self reactive
B cells. However, there was no apparent expansion of B cells in
mice expressing an ENU induced germline CARD11M365K mutation. In
vitro assays with B cells showed that CARD11M365K has stronger
NFkB and growth inducing effects than CARD11E127G. Together,
these results reveal an intriguing difference between the effects
of overactive CARD11 signalling in humans and mice. The
availability of an ENU induced CARD11M365K mutant mouse strain
presents opportunities to further study the effects of overactive
CARD11 in lymphocytes.
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Keywords
CARD11, NFkB, Lymphoma, Tolerance, Immunology, Cancer
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