S4and Fig. work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas. infection, and also in the ocular adnexa, lung, salivary glands, intestinal tract, skin, thyroid, and genitourinary tract, and are associated with chronic microbial infections or autoimmune disorders. MALT lymphomas show a typical histopathological picture composed of a heterogeneous neoplastic B-cell population that arises from the marginal zone of reactive B-cell follicles, extends to the interfollicular region, and infiltrates the epithelium, forming the characteristic lymphoepithelial lesions. Additionally, these lymphomas frequently show a prominent plasmacytic differentiation (1C3). Genetically, MALT lymphomas are mainly associated with two chromosomal translocations involving the gene. The t(11;18)(q21;q21), which generates an API2-MALT1 fusion transcript, occurs in up to 30% of the cases, whereas the t(14;18)(q32;q21) results in the immunoglobulin H (translocation and Ibotenic Acid is detected in 15C20% of Ibotenic Acid the cases (4C6). A third translocation, the t(1;14)(p22;q32), forms a B-cell fusion and is present in 1% of MALT lymphomas. All of these translocations lead to the activation of NF-B, which regulates target genes involved in immune responses to foreign antigens (7). In B lymphocytes, MALT1 is part of the CARD11/BCL10/MALT1 (CBM) complex, a mediator of the stimulation of the B-cell antigen receptor (BCR). MALT1 mediates the activation of the IB kinase (IKK) complex, leading to the release and nuclear translocation of NF-B. Remarkably, the caspase-like domain of MALT1 shows proteolytic activity and can cleave BCL10 and several NF-B inhibitors, resulting in NF-B activation (7C9). In MALT lymphomas, it is assumed that underlying chronic infection/inflammation causes persistent BCR-mediated NF-B activation that promotes B-lymphocyte expansion and accumulation in extranodal tissues, ultimately resulting in clonal lymphoma development (1, 3). Emerging data also implicate the CBM complex in the pathogenesis of diffuse large cell lymphoma of activated B cells (ABC-DLBCL), a distinct lymphoma subtype that can be distinguished from the germinal center B-cell-like (GCB)-DLBCL (10, 11). Like in MALT lymphomas, a hallmark of ABC-DLBCL is the constitutive signaling of the NF-B pathway, which is caused by mutations in various genes regulating NF-B, including activating mutations of (11). Notably, Ibotenic Acid mutations in and genes have been also found in MALT lymphomas, suggesting a molecular link between ABC-DLBCL and MALT lymphoma (11). However, this relationship has not been proved experimentally. Despite these evidences, a causative role for Ibotenic Acid MALT1 in the development of MALT lymphoma has not been demonstrated. Indeed, the expression of API2-MALT1 or BCL10 in B lymphocytes did not induce lymphoma in mice (12, 13), suggesting that NF-B activation in B cells may not be sufficient to promote malignant transformation. The lack of genetically engineered human-like MALT lymphoma models has hampered a better understanding of the disease pathogenesis and the development of MALT1-targeted therapies, the relevance of which to the treatment of ABC-DLBCL, an aggressive lymphoma that responds poorly to current immunochemotherapies, has already been highlighted using in vitro cell models (14, 15). In this work, we show that human MALT lymphoma pathogenesis can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of in lymphomagenesis. Furthermore, our study establishes a molecular link between MALT lymphoma and ABC-DLBCL and provides mouse models to test therapies targeting MALT1. Results MALT1 Shows Oncogenic Properties in Primitive Hematopoietic Cells. Given that the expression of the MALT lymphoma-related genes in mouse B lymphocytes does not induce lymphoma development, we first explored whether MALT1, BCL10, or API2-MALT1 could be tumorigenic in more primitive hematopoietic cells. Human full-length and genes and the fusion gene were stably transfected into murine IL3-dependent hematopoietic BaF3 cells activated with anti-mouse IgM, anti-mouse CD40 antibody, and recombinant mIL4. Isolated single-cell clones expressing genes exhibited higher NF-B activation with respect to control cells, but only and into BALB/c nude mice revealed that only and gene in the hematopoietic stem/progenitor cell compartment of C57BL/6 CBA mice Ibotenic Acid (Fig. S2mRNA expression levels by RT-PCR showed expression of the exogenous human transgene in Sca1+Lin? hematopoietic/stem cells purified from the bone marrow (BM) of Sca1-MALT1 mice, but not in Rabbit Polyclonal to CNGB1 wild-type (WT) littermates (Fig. S2expression was detected in Sca1+Lin? cells but not in other lymphoid cell subpopulations, as determined by quantitative real-time PCR analysis performed in cells isolated from BM, spleen and lymph nodes (and and = 0.0007; line 86B vs. WT, = 0.0026;.