2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Mantle cell lymphoma (MCL) is an incurable aggressive B cell lymphoma for which mouse models are currently lacking. Pieters et al. show that Ccnd2 overexpression and p53 loss in mice induce B1a-derived MCL-like lymphomas that are sensitive to MALT1 inhibition.

          Abstract

          Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor long-term overall survival. Currently, MCL research and development of potential cures is hampered by the lack of good in vivo models. MCL is characterized by recurrent translocations of CCND1 or CCND2, resulting in overexpression of the cell cycle regulators cyclin D1 or D2, respectively. Here, we show, for the first time, that hematopoiesis-specific activation of cyclin D2 is sufficient to drive murine MCL-like lymphoma development. Furthermore, we demonstrate that cyclin D2 overexpression can synergize with loss of p53 to form aggressive and transplantable MCL-like lymphomas. Strikingly, cyclin D2–driven lymphomas display transcriptional, immunophenotypic, and functional similarities with B1a B cells. These MCL-like lymphomas have B1a-specific B cell receptors (BCRs), show elevated BCR and NF-κB pathway activation, and display increased MALT1 protease activity. Finally, we provide preclinical evidence that inhibition of MALT1 protease activity, which is essential for the development of early life–derived B1a cells, can be an effective therapeutic strategy to treat MCL.

          Graphical Abstract

          Related collections

          Most cited references91

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

          In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            STAR: ultrafast universal RNA-seq aligner.

            Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

              Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
                Bookmark

                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: Investigation
                Role: ConceptualizationRole: Writing - review & editing
                Role: InvestigationRole: Validation
                Role: Investigation
                Role: Formal analysis
                Role: Formal analysisRole: Visualization
                Role: InvestigationRole: Resources
                Role: ResourcesRole: Validation
                Role: Resources
                Role: Investigation
                Role: Formal analysis
                Role: InvestigationRole: Writing - review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: ResourcesRole: Supervision
                Role: Data curationRole: SupervisionRole: Writing - review & editing
                Role: InvestigationRole: ResourcesRole: Writing - review & editing
                Role: InvestigationRole: Methodology
                Role: MethodologyRole: ResourcesRole: Writing - review & editing
                Role: ResourcesRole: ValidationRole: Writing - review & editing
                Role: Formal analysisRole: MethodologyRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing - original draftRole: Writing - review & editing
                Journal
                J Exp Med
                J Exp Med
                jem
                The Journal of Experimental Medicine
                Rockefeller University Press
                0022-1007
                1540-9538
                04 October 2021
                18 August 2021
                : 218
                : 10
                : e20202280
                Affiliations
                [1 ] Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
                [2 ] Center for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium
                [3 ] Cancer Research Institute Ghent, Ghent, Belgium
                [4 ] Center for Inflammation Research, Flemish Institute for Biotechnology, Ghent, Belgium
                [5 ] Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
                [6 ] Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
                [7 ] Department of Hematology, Ghent University Hospital, Ghent, Belgium
                [8 ] Center for Innovation and Stimulation of Drug Discovery Leuven, Leuven, Belgium
                [9 ] Center for Drug Design and Discovery, Catholic University of Leuven, Leuven, Belgium
                [10 ] Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
                [11 ] Department of Pathology, Ghent University Hospital, Ghent, Belgium
                Author notes
                Correspondence to Pieter Van Vlierberghe: pieter.vanvlierberghe@ 123456ugent.be

                Disclosures: R. Beyaert reported grants from Galapagos nv outside the submitted work; in addition, R. Beyaert had a patent to WO09065897 issued. No other disclosures were reported.

                [*]

                P. Van Vlierberghe and S. Goossens contributed equally to this paper.

                Author information
                https://orcid.org/0000-0002-2958-0104
                https://orcid.org/0000-0003-4256-9775
                https://orcid.org/0000-0001-5305-1651
                https://orcid.org/0000-0001-5282-7278
                https://orcid.org/0000-0003-3545-4283
                https://orcid.org/0000-0001-7230-3690
                https://orcid.org/0000-0002-7385-0546
                https://orcid.org/0000-0002-5025-9817
                https://orcid.org/0000-0002-8172-5649
                https://orcid.org/0000-0002-0007-382X
                https://orcid.org/0000-0001-7033-9569
                https://orcid.org/0000-0002-6499-4572
                https://orcid.org/0000-0002-0102-4667
                https://orcid.org/0000-0002-5319-6751
                https://orcid.org/0000-0003-4842-944X
                https://orcid.org/0000-0001-7170-1910
                https://orcid.org/0000-0001-6692-5004
                https://orcid.org/0000-0001-6320-6020
                https://orcid.org/0000-0001-8175-2930
                https://orcid.org/0000-0001-5897-2054
                https://orcid.org/0000-0001-5770-2458
                https://orcid.org/0000-0002-5704-582X
                https://orcid.org/0000-0003-2664-3357
                https://orcid.org/0000-0001-9063-7205
                https://orcid.org/0000-0002-5693-8570
                Article
                jem.20202280
                10.1084/jem.20202280
                8377631
                34406363
                0beb7b57-83e2-4cb2-81c2-ca16a81ca341
                © 2021 Pieters et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 24 October 2020
                : 24 February 2021
                : 21 July 2021
                Page count
                Pages: 18
                Funding
                Funded by: Fund for Scientific Research Flanders;
                Funded by: Ghent University Research Fund;
                Funded by: Research Foundation – Flanders;
                Award ID: FWO-1244321N
                Categories
                Article
                Leukemia & Lymphoma

                Medicine
                Medicine

                Comments

                Comment on this article