The role of MALT1 in the molecular pathogenesis of mantle cell lymphoma
Final Report Abstract
With a median age of 65 years at diagnosis, mantle cell lymphoma (MCL) is a disorder of the elderly. Although MCL accounts for only 8-10% of all malignant lymphoma cases, it contributes disproportionately to lymphoma mortality, due to its often aggressive clinical course and lack of curative therapeutic regimens. Despite recent advances in the understanding of the biology of MCL, many pathogenetic mechanisms and biologic features remain unknown. Within the funded project, we aimed to elucidate the role of the paracaspase MALT1 in the molecular pathogenesis of MCL. Here we show that a subset of MCLs is addicted to MALT1 signaling, as its inhibition by either RNA or pharmacologic interference induced cytotoxicity both in vitro and in vivo. Gene expression profiling following MALT1 inhibition demonstrated that MALT1 controls a MYC-driven gene expression network predominantly through increasing MYC protein stability. Thus, our analyses identify a previously unappreciated regulatory mechanism of MYC expression. MYC itself is pivotal for MCL survival as its downregulation and pharmacologic inhibition induced cytotoxicity in all MCL models. Collectively, these results provide a strong mechanistic rationale to investigate the therapeutic efficacy of targeting the MALT1-MYC axis in MCL patients.
Publications
- B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma. Blood. 2017 Jan 19; 129 (3): 333-346
Dai B., Grau M., Juilland M., Klener P., Höring E., Molinsky J., Schimmack G., Aukema S.M., Hoster E., Vogt N., Staiger A.M., Erdmann T., Xu W., Erdmann K., Dzyuba N., Madle H., Berdel W.E., Trneny M., Dreyling M., Jöhrens K., Lenz P., Rosenwald A., Siebert R., Tzankov A., Klapper W., Anagnostopoulos I., Krappmann D., Ott G., Thome M., Lenz G.
(See online at https://doi.org/10.1182/blood-2016-05-718775) - Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL. Blood. 2017; 130 (3): 310-322
Erdmann T., Klener P., Lynch J.T., Grau M., Vočková P., Molinsky J., Tuskova D., Hudson K., Polanska U.M., Grondine M., Mayo M., Dai B., Pfeifer M., Erdmann K., Schwammbach D., Zapukhlyak M., Staiger A.M., Ott G., Berdel W.E., Davies B.R., Cruzalegui F., Trneny M., Lenz P., Barry S.T., Lenz G.
(See online at https://doi.org/10.1182/blood-2016-12-758599) - The molecular pathogenesis of mantle cell lymphoma. Leukemia & Lymphoma. 2017; 58 (7): 1530-1537
Vogt N., Dai B., Erdmann T., Berdel W.E., Lenz G.
(See online at https://doi.org/10.1080/10428194.2016.1248965) - Dissection of gene expression datasets into clinically relevant interaction signatures via high-dimensional correlation maximization. Nature Communications. 2019;10 (1): 5417
Grau M., Lenz G., Lenz P.
(See online at https://doi.org/10.1038/s41467-019-12713-5)
