title: Selective expansion of marginal zone B cells in Emicro-API2-MALT1 mice is linked to enhanced IkappaB kinase gamma polyubiquitination.
abstract: The translocation t(11;18)(q21;q21) that generates an API2-MALT1 fusion protein is the most common structural abnormality among the genetic defects reported in mucosa-associated lymphoid tissue (MALT)-type lymphomas, and its presence correlates with the apparent lack of further genetic instability or chromosomal imbalances. Hence, constitutive nuclear factor-kappaB (NF-kappaB) activation induced by the API2-MALT1 fusion protein is considered essential for B-cell transformation. To examine its role in B-cell development and lymphomagenesis, Emu-API2-MALT1 transgenic mice were produced. Our data show that expression of the API2-MALT1 fusion protein alone is not sufficient for the development of lymphoma masses within 50 weeks. Nevertheless, API2-MALT1 expression affected B-cell maturation in the bone marrow and triggered the specific expansion of splenic marginal zone B cells. Polyubiquitination of IkappaB kinase gamma (IKKgamma), indicative for enhanced NF-kappaB activation, was increased in splenic lymphocytes and promoted the survival of B cells ex vivo. In addition, we show that the API2-MALT1 fusion resided in the cholesterol- and sphingolipid-enriched membrane microdomains, termed lipid rafts. We provide evidence that association of the MALT1 COOH terminal with the lipid rafts, which is mediated by the API2 portion, is sufficient to trigger NF-kappaB activation via enhanced polyubiquitination of IKKgamma. Taken together, these data support the hypothesis that the API2-MALT1 fusion protein can contribute to MALT lymphoma formation via increased NF-kappaB activation.
authors.affiliation: Center for Human Genetics, Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Catholic University of Leuven, Leuven, Belgium. Mathijs.Baens@Med.KULeuven.be
authors.forename: Mathijs
authors.initials: M
authors.lastname: Baens
authors.forename: Sabine
authors.initials: S
authors.lastname: Fevery
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.forename: Heidi
authors.initials: H
authors.lastname: Noels
authors.forename: Sofie
authors.initials: S
authors.lastname: Hagens
authors.forename: Vicky
authors.initials: V
authors.lastname: Broeckx
authors.forename: An D
authors.initials: AD
authors.lastname: Billiau
authors.forename: Christiane
authors.initials: C
authors.lastname: De Wolf-Peeters
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C415943:API2-MALT1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D014452:Ubiquitins; D051550:I-kappa B Kinase