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Wimberger, N. ; Ober, F. ; Avar, G. ; Grau, M.* ; Xu, W.* ; Lenz, G.* ; Menden, M.P. ; Krappmann, D.

Oncogene-induced MALT1 protease activity drives post-transcriptional gene expression in malignant lymphomas.

Blood 142, 1985-2001 (2023)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Constitutive MALT1 activity drives survival of malignant lymphomas addicted to chronic B-cell receptor (BCR) signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. While MALT1 scaffolding induces NF-kB-dependent survival signaling, MALT1 protease function is thought to augment NF-kB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-kB transcriptional responses, but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and non-enzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease-dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. The data hint that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces post-transcriptional upregulation of many genes including NFKBIZ/IkBz, NFKBID/IkBNS and ZC3H12A/Regnase-1 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives post-transcriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and post-transcriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Nf-kappa-b; Cell-receptor; Activation; Cleavage; Regnase-1; Survival; Lymphocytes; Mechanisms; Inhibitors; Mutations
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Zeitschrift Blood
Quellenangaben Band: 142, Heft: 23, Seiten: 1985-2001 Artikelnummer: , Supplement: ,
Verlag American Society of Hematology
Verlagsort 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)
Institute of Computational Biology (ICB)
Förderungen Deutsche Krebshilfe award
Deutsche Forschungsgemeinschaft
European Union's Horizon 2020 Research and Innovation Program
Federal Ministry of Education and Research-funded German Network for Bioinformatics Infrastructure