RESUMO
Constitutive mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) activity drives survival of malignant lymphomas addicted to chronic B-cell receptor signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. Although MALT1 scaffolding induces NF-κB-dependent survival signaling, MALT1 protease function is thought to augment NF-κB 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-κB transcriptional responses but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and nonenzymatic 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 suggest that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces posttranscriptional upregulation of many genes including NFKBIZ/IκBζ, NFKBID/IκBNS, 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 an mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives posttranscriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in MALT lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and posttranscriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease-selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.
Assuntos
Linfoma de Zona Marginal Tipo Células B , Linfoma Difuso de Grandes Células B , Humanos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Oncogenes , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismoRESUMO
Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analyse 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detect the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constitutes drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduces anticipated associations, and in addition, we find that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.