Mechanismen der NF-kappaB Aktivierung beim diffus großzelligen B Zell Lymphom
Zusammenfassung der Projektergebnisse
Activated B cell like (ABC) diffuse large B cell lymphoma display an aggressive form of Non-Hodgkin lymphoma (NHL) featuring constitutive active NF-kB signaling. CARD11, BCL10, and Malt1 (CBM) complex-mediated activation of the NF-kB pathway is essential for tumor cell survival, however, therapeutic intervention applying selective inhibitors targeting IKK kinases downstream of the CBM complex still remain a limiting factor due to high toxicities. Therefore, the investigation of optional drug targets is highly advisable. In order to investigate consequences of active CARD11 mutants in vivo and to understand its signaling outcomes in more detail, conditional knock-in mice were generated, allowing modeling of cell-typedefined expression of a patient-derived CARD11(L225LI) mutant protein. Early B cell stage expression of CARD11(L225LI) induced an aggressive lymphoproliferative inflammatory disease resulting in sudden death within approximately one week of age. Long-term observation upon germinal center B cell stage expression eventually resulted in a clonal malignant outgrowth of phenotypically mature, class-switched B cells. Due to Cre-leakiness, B cell lymphoma were accompanied by an abnormal T cell outgrowth harboring a Tfh-like phenotype. In both models, disease lethality was rescued by breeding onto the Bcl10- or MALT-knockout mouse strains, indicating disease dependency on a functional CBM complex formation and downstream signaling. Furthermore, crosses onto MALT1 paracaspase mutant (PM) mice again demonstrated that early disease onset was blocked, concluding that not only the scaffold but also the enzymatic activity of MALT1 paracaspase plays an essential role in these in vivo models. On a molecular level, CARD11 constitutively induced not only NF-kB but also c-Jun N-terminal kinase (JNK) signaling pathways, both, when blocked, negatively affecting cell survival and proliferation of CARD11(L225LI)-expressing B cells. This was not only observed in primary B cells isolated from knock-in mouse models but also detected in a significant percentage of investigated ABC-type DLBCL lymphoma cell lines. In vitro JNK inhibitor treatment reduced cell survival, emphasizing the JNK signaling pathway as a potential treatment alternative next to NF-kB pathway components, especially as a target option for JNK-sensitive DLBCL subtypes. Taken together, our results demonstrated that in vivo expression of the DLBCL-derived CARD11 (L225Li) mutation led to constitutive CBM-mediate NF-kB signaling and in its additive engagement of the JNK signaling cascade triggered an aggressive lymphoproliferative disease, and resulted long-term in malignant mature B cell lymphoma. We especially identify the JNK signaling pathway as an alternative druggable target for future therapeutical approaches.
Projektbezogene Publikationen (Auswahl)
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(2013). A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J Allergy Clin Immunol 132, 151-8
Jabara, H.H., Ohsumi, T., Chou, J., Massaad, M.J., Benson, H., Megarbane, A., Chouery, E., Mikhael, R., Gorka, O., Gewies, A., Portales, P., Nakayama, T., Hosokawa, H., Revy, P., Herrod, H., Le Deist, F., Lefranc, G., Ruland, J., Geha, R.S.
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(2014). Uncoupling malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. Cell Rep 9, 1292-305
Gewies, A., Gorka, O., Bergmann, H., Pechloff, K., Petermann, F., Jeltsch, K.M., Rudelius, M., Kriegsmann, M., Weichert, W., Horsch, M., Beckers, J., Wurst, W., Heikenwalder, M., Korn, T., Heissmeyer, V., Ruland, J.
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(2015). Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-kappaB and JNK activation. Proc Natl Acad Sci USA 112, E7230-8
Knies, N., Alankus, B., Weilemann, A., Tzankov, A., Brunner, K., Ruff, T., Kremer, M., Keller, U.B., Lenz, G., Ruland, J.
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(2016). Vav Proteins Are Key Regulators of Card9 Signaling for Innate Antifungal Immunity. Cell Rep 17, 2572-2583
Roth, S., Bergmann, H., Jaeger, M., Yeroslaviz, A., Neumann, K., Koenig, P.A., Prazeres da Costa, C., Vanes, L., Kumar, V., Johnson, M., Menacho-Marquez, M., Habermann, B., Tybulewicz, V.L., Netea, M., Bustelo, X.R., Ruland, J.
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(2017). Card9-dependent IL-1beta regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer. Eur J Immunol 47, 1342-1353
Bergmann, H., Roth, S., Pechloff, K., Kiss, E.A., Kuhn, S., Heikenwalder, M., Diefenbach, A., Greten, F.R., Ruland, J.
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(2017). PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552, 121-125
Wartewig, T., Kurgyis, Z., Keppler, S., Pechloff, K., Hameister, E., Ollinger, R., Maresch, R., Buch, T., Steiger, K., Winter, C., Rad, R., Ruland, J.
