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.
- MeSH
- buněčná smrt MeSH
- heterografty MeSH
- kaspasy metabolismus fyziologie MeSH
- lidé MeSH
- lymfom z plášťových buněk metabolismus MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny metabolismus fyziologie MeSH
- NF-kappa B metabolismus MeSH
- protein MALT1 MeSH
- protoonkogenní proteiny c-myc metabolismus MeSH
- receptory antigenů B-buněk fyziologie MeSH
- regulace genové exprese u nádorů MeSH
- signální transdukce MeSH
- viabilita buněk MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.
- MeSH
- antitumorózní látky farmakologie MeSH
- apoptóza účinky léků MeSH
- difúzní velkobuněčný B-lymfom klasifikace farmakoterapie genetika patologie MeSH
- fixní kombinace léků MeSH
- fosfatidylinositol-3-kinasy genetika metabolismus MeSH
- fosfohydroláza PTEN nedostatek genetika MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- inhibitory proteinkinas farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- myši MeSH
- NF-kappa B antagonisté a inhibitory genetika metabolismus MeSH
- orgánová specificita MeSH
- oxadiazoly farmakologie MeSH
- piperidiny farmakologie MeSH
- protoonkogenní proteiny c-akt antagonisté a inhibitory genetika metabolismus MeSH
- protoonkogenní proteiny c-myc antagonisté a inhibitory genetika metabolismus MeSH
- pyrazoly farmakologie MeSH
- pyrimidiny farmakologie MeSH
- pyrroly farmakologie MeSH
- regulace genové exprese u nádorů * MeSH
- signální transdukce MeSH
- synergismus léků MeSH
- tyrosinkinasy antagonisté a inhibitory genetika metabolismus MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
