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B-cell receptor–driven MALT1 activity regulates MYC signaling in mantle cell lymphoma

Beiying Dai, Michael Grau, Mélanie Juilland, Pavel Klener, Elisabeth Höring, Jan Molinsky, Gisela Schimmack, Sietse M. Aukema, Eva Hoster, Niklas Vogt, Annette M. Staiger, Tabea Erdmann, Wendan Xu, Kristian Erdmann, Nicole Dzyuba, Hannelore Madle, Wolfgang E. Berdel, Marek Trneny, Martin Dreyling, Korinna Jöhrens, Peter Lenz, Andreas Rosenwald, Reiner Siebert, Alexandar Tzankov, Wolfram Klapper, Ioannis Anagnostopoulos, Daniel Krappmann, German Ott, Margot Thome and Georg Lenz

Key Points

  • MALT1 protease activity stabilizes MYC.

  • The MALT1-MYC network might represent a therapeutic target for MCL patients.

Abstract

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by poor clinical outcome. Recent studies revealed the importance of B-cell receptor (BCR) signaling in maintaining MCL survival. However, it remains unclear which role MALT1, an essential component of the CARD11-BCL10-MALT1 complex that links BCR signaling to the NF-κB pathway, plays in the biology of MCL. Here we show that a subset of MCLs is addicted to MALT1, 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 an MYC-driven gene expression network predominantly through increasing MYC protein stability. Thus, our analyses identify a previously unappreciated regulatory mechanism of MYC expression. Investigating primary mouse splenocytes, we could demonstrate that MALT1-induced MYC regulation is not restricted to MCL, but represents a common mechanism. MYC itself is pivotal for MCL survival because 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.

  • Submitted May 25, 2016.
  • Accepted November 11, 2016.
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