Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma

ABSTRACT: A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy. HBL-1 cells (n=8) were treated with IkB kinase beta inhibitor MLN120B (25 micromolar; Calbiochem) for 2h, 3h, 4h, 6h, 8h, 12h, 16h, and 24h (Cy5) and their gene expression compared to vehicle-treated cells (DMSO, Cy3). HBL-1 cells (n=4) and OCI-Ly3 cells (n=4) were treated with MALT1 inhibitor z-VRPR-fmk (50 micromolar; Alexis Biochemicals) for 6h, 12h, 24h, and 30h (Cy5) and their gene expression compared to vehicle-treated cells (DMSO, Cy3).

ORGANISM(S): Homo sapiens

SUBMITTER: Louis Staudt

PROVIDER: E-GEOD-41034 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma.

Hailfinger Stephan S Lenz Georg G Ngo Vu V Posvitz-Fejfar Anita A Rebeaud Fabien F Guzzardi Montserrat M Penas Eva-Maria Murga EM Dierlamm Judith J Chan Wing C WC Staudt Louis M LM Thome Margot M

Proceedings of the National Academy of Sciences of the United States of America 20091106 47

A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is ...[more]

PMID: 19897720

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Project description:The ABC subtype of diffuse large B cell lymphoma (DLBCL) remains the least curable form of this lymphoma despite recent advances in therapy. We have combined structural and functional genomics to triangulate on new oncogenic mechanisms and devise new therapeutic strategies. RNA interference screen revealed a dependence of ABC DLBCL cell lines on MYD88 and IRAK1. High throughput resequencing of RNA (RNA-Seq) revealed frequent somatic mutations in MYD88 that preferentially occurred in the ABC DLBCL subtype. Remarkably, one third of ABC DLBCL tumor samples harbored the same amino acid substitution, L265P, in the MYD88 TIR domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in two other DLBCL subtypes, but was observed in 9% of MALT lymphomas. At a lower frequency, multiple other mutations were observed in the MYD88 TIR domain, occurring in both the ABC and GCB subtypes of DLBCL. Survival of ABC DLBCL lines bearing the L265P mutation was sustained by the mutant but not wild type MYD88 isoform, demonstrating that this MYD88 mutant is oncogenic and gain-of-function. The MYD88 L265P mutant assembled a protein complex that spontaneous triggers the phosphorylation of IRAK1, leading to NF-kB signaling, secretion of the cytokines IL-6, IL-10 and interferon-b, and JAK kinase signaling. These findings demonstrate that the MYD88 signaling pathway is integral to the pathogenesis of ABC DLBCL, providing a genetic rationale for therapeutic targeting of the MYD88 signaling pathway in this lymphoma subtype. To generate a gene expression signature of MYD88 signaling in ABC DLBCL, the HBL-1 cell line was transduced with retroviral vectors expressing either shMYD88-4 or shMYD88-7. Following puromycin selection, shRNA expression was induced for 24 or 48 hours and gene expression was measured, comparing uninduced (Cy3) to induced (Cy5) cells, using genome-wide Agilent 4x44K oligonucleotide microarrays. A signature of NF-kB signaling in ABC DLBCL was generated by treating HBL-1 cells with the IkB kinase beta inhibitor MLN120B for 2h, 3h, 4h, 6h, 8h, 12h, 16h, and 24h (Cy5), and comparing their gene expression to untreated cells (Cy3). A signature of JAK signaling in ABC DLBCL was generated by treating HBL-1 cells with JAK inhibitor I (5 micromolar; Calbiochem) for 2h, 4h, 6h, and 8h (Cy5) and comparing their gene expression to vehicle-treated cells (DMSO, Cy3). RNA-Seq data not provided.

Project description:In this study, we subjected the phenomenon of fractional killing in a clonal population of TRAIL-sensitive cells to careful analysis. We asked whether cells that survive initial exposure to TRAIL are sensitive or resistant to subsequent treatment with TRAIL or other apoptosis-inducing agents. We observed that TRAIL survivor cells were highly resistant to a subsequent treatment with TRAIL 24hr later but that this resistance disappeared following several days in culture. Resistance did not involve downregulation of TRAIL receptors and extended to death ligands that bind different classes of receptors: TRAIL survivors were transiently resistant to FasL and vice versa. Gene expression analysis revealed that NF-kB-mediated inflammatory genes were activated in transiently resistant survivor cells leading to an inflammatory phenotype, but resistance was mediated by an independent mechanism related to changes in signaling at the DISC. Periodic exposure to TRAIL sustained resistance, demonstrating a component of induced survival signaling leading to transient acquired resistance to TRAIL. Based on these results we propose that TRAIL treatment leads to a transient adaptation in survivor cells that can be sustained in cells exposed to long-term TRAIL treatments, leading to acquired resistance. Minimizing the impact of cell-to-cell variability on TRAIL-mediated killing will thus require appropriate spacing of stimuli as well as the use of additional agents that inhibit pro-survival pathways. RNA was collected from Control (untreated) MCF10A cells, Survivors of TRAIL treatment (Day 1), Reset cells (survivors on Day 7), and Repeat cells (Survivors treated with TRAIL on 2 subsequent days). RNA was also collected from Control and Survivor MCF10A cells expressing an IKB-super-repressor construct (Addgene, Plasmid 15291; Boehm et al., 2007), or treated with caspase inhibitors. Three biological experiments were performed (on different days) with 1-2 replicates of each sample collected for each experiment. The total number of samples was 31, on 4 IlluminaRef8 BeadChips (one sample was from an unrelated experiment and was not included). The number of total replicates for each treatment is as follows: Control (7); Survivors (6); Reset (3); Repeat (3); Control-IKB-super-repressor (2); Survivors-IKB-super-repressor (2); Control-zVADinhibitor (2); Survivors-zVADinhibitor (2); Control-IETDinhibitor (2); Survivors-IETDinhibitor (2).

Dataset Information

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma

Publications

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma.

Similar Datasets

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