TY - JOUR
T1 - MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-κB-dependent proliferative advantage and resistance against FAS-induced cell death in B cells
AU - Ho, Liza
AU - Davis, R. Eric
AU - Conne, Béatrice
AU - Chappuis, Richard
AU - Berczy, Margaret
AU - Mhawech, Paulette
AU - Staudt, Louis M.
AU - Schwaller, Juerg
PY - 2005/4/1
Y1 - 2005/4/1
N2 - The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overex-pression. Various approaches have implicated these proteins in nuclear factor κB (NF-κB) signaling, but this has not been shown experimentally in human B cells, Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NF-κB signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]-containing membrane-associated guanylate kinase [MAGUK] 1). API2-MALT1 and exogenous MALT1 increased constitutive NF-κB activity and enhanced IκB kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)-induced death, consistent with increases in NF-κB cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative IκBα mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NF-κB activity. Our findings support a model in which NF-κB signaling, once activated in a CD40-dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2-MALT1 fusion.
AB - The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overex-pression. Various approaches have implicated these proteins in nuclear factor κB (NF-κB) signaling, but this has not been shown experimentally in human B cells, Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NF-κB signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]-containing membrane-associated guanylate kinase [MAGUK] 1). API2-MALT1 and exogenous MALT1 increased constitutive NF-κB activity and enhanced IκB kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)-induced death, consistent with increases in NF-κB cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative IκBα mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NF-κB activity. Our findings support a model in which NF-κB signaling, once activated in a CD40-dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2-MALT1 fusion.
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U2 - 10.1182/blood-2004-06-2297
DO - 10.1182/blood-2004-06-2297
M3 - Article
C2 - 15598810
AN - SCOPUS:15944414157
SN - 0006-4971
VL - 105
SP - 2891
EP - 2899
JO - Blood
JF - Blood
IS - 7
ER -