207 results on '"Birgitta Sander"'
Search Results
2. Whole-genome informed circulating tumor DNA analysis by multiplex digital PCR for disease monitoring in B-cell lymphomas: a proof-of-concept study
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Zahra Haider, Tove Wästerlid, Linn Deleskog Spångberg, Leily Rabbani, Cecilia Jylhä, Birna Thorvaldsdottir, Aron Skaftason, Hero Nikdin Awier, Aleksandra Krstic, Anna Gellerbring, Anna Lyander, Moa Hägglund, Ashwini Jeggari, Georgios Rassidakis, Kristina Sonnevi, Birgitta Sander, Richard Rosenquist, Emma Tham, and Karin E. Smedby
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cell-free DNA (cfDNA) ,whole genome sequence (WGS) ,liquid biopsy ,lymphoma ,measurable (minimal) residual disease (MRD) ,droplet digital (ddPCR) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionAnalyzing liquid biopsies for tumor-specific aberrations can facilitate detection of measurable residual disease (MRD) during treatment and at follow-up. In this study, we assessed the clinical potential of using whole-genome sequencing (WGS) of lymphomas at diagnosis to identify patient-specific structural (SVs) and single nucleotide variants (SNVs) to enable longitudinal, multi-targeted droplet digital PCR analysis (ddPCR) of cell-free DNA (cfDNA).MethodsIn 9 patients with B-cell lymphoma (diffuse large B-cell lymphoma and follicular lymphoma), comprehensive genomic profiling at diagnosis was performed by 30X WGS of paired tumor and normal specimens. Patient-specific multiplex ddPCR (m-ddPCR) assays were designed for simultaneous detection of multiple SNVs, indels and/or SVs, with a detection sensitivity of 0.0025% for SV assays and 0.02% for SNVs/indel assays. M-ddPCR was applied to analyze cfDNA isolated from serially collected plasma at clinically critical timepoints during primary and/or relapse treatment and at follow-up.ResultsA total of 164 SNVs/indels were identified by WGS including 30 variants known to be functionally relevant in lymphoma pathogenesis. The most frequently mutated genes included KMT2D, PIM1, SOCS1 and BCL2. WGS analysis further identified recurrent SVs including t(14;18)(q32;q21) (IGH::BCL2), and t(6;14)(p25;q32) (IGH::IRF4). Plasma analysis at diagnosis showed positive circulating tumor DNA (ctDNA) levels in 88% of patients and the ctDNA burden correlated with baseline clinical parameters (LDH and sedimentation rate, p-value
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- 2023
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3. ADAR1-mediated RNA editing promotes B cell lymphomagenesis
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Riccardo Pecori, Weicheng Ren, Mohammad Pirmoradian, Xianhuo Wang, Dongbing Liu, Mattias Berglund, Wei Li, Rafail Nikolaos Tasakis, Salvatore Di Giorgio, Xiaofei Ye, Xiaobo Li, Annette Arnold, Sandra Wüst, Martin Schneider, Karthika-Devi Selvasaravanan, Yvonne Fuell, Thorsten Stafforst, Rose-Marie Amini, Kristina Sonnevi, Gunilla Enblad, Birgitta Sander, Björn Engelbrekt Wahlin, Kui Wu, Huilai Zhang, Dominic Helm, Marco Binder, F. Nina Papavasiliou, and Qiang Pan-Hammarström
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Genetics ,Molecular biology ,Epigenetics ,Omics ,Transcriptomics ,Science - Abstract
Summary: Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of RNA editing to DLBCL pathogenesis. We observed that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumors can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as the RIG-I-like pathway. In this context, we show that ADAR1-mediated editing within MAVS transcript positively correlates with MAVS protein expression levels, associating with increased interferon/NF-κB signaling and T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3′UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing.
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- 2023
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4. Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment
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Wendy B. C. Stevens, G. Tjitske Los-de Vries, Carole Langois-Jacques, Andrew J. Clear, Phylicia Stathi, Birgitta Sander, Andreas Rosenwald, Maria Calaminici, Eva Hoster, Wolfgang Hiddemann, Philippe Gaulard, Gilles Salles, Wolfram Klapper, Luc Xerri, Catherine Burton, Reuben M. Tooze, Alexandra G. Smith, Christian Buske, David W. Scott, Yasodha Natkunam, Ranjana Advani, Laurie H. Sehn, John Raemaekers, John Gribben, Sandra Lockmer, Eva Kimby, Marie José Kersten, Delphine Maucort-Boulch, Bauke Ylstra, Erik van Dijk, and Daphne de Jong
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. Real-world data on treatment and outcomes of patients with primary mediastinal large B-cell lymphoma: a Swedish lymphoma register study
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Tove Wästerlid, Sverker Hasselblom, Joel Joelsson, Caroline E. Weibull, Georgios Rassidakis, Birgitta Sander, and Karin E. Smedby
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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6. Marginal zone lymphoma expression of histidine‐rich glycoprotein correlates with improved survival
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Tor Persson Skare, Elin Sjöberg, Mattias Berglund, Ross O Smith, Francis P Roche, Cecilia Lindskog, Birgitta Sander, Ingrid Glimelius, Alex R Gholiha, Gunilla Enblad, Rose‐Marie Amini, and Lena Claesson‐Welsh
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alpha defensin 1 ,gene expression ,histidine rich glycoprotein ,marginal zone lymphoma ,survival ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Purpose The abundant hepatocyte‐expressed plasma protein histidine‐rich glycoprotein (HRG) enhances antitumor immunity by polarizing inflammatory and immune cells in several mouse models, however, the clinical relevance of HRG in human cancer is poorly explored. The expression and role of HRG in human B‐cell lymphomas was investigated in order to find new tools for prognosis and treatment. Findings Immunohistochemical (IHC) analysis and RNA hybridization of tissue microarrays showed that (i) HRG was expressed by tumor cells in marginal zone lymphoma (MZL), in 36% of 59 cases. Expression was also detected in follicular lymphoma (22%), mantle cell lymphoma (19%), and indiffuse large B‐cell lymphoma (DLBCL;5%) while primary CNS lymphoma (PCNSL) lacked expression of HRG. (ii) MZL patients positive for HRG showed a superior overall survival outcome (HR = 0.086, 95% CI = 0.014‐0.518, P‐value = .007), indicating a protective role for HRG independent of stage, age and sex. (iii) HRG‐expressing MZL displayed significantly increased transcript and protein levels of the host defense peptide alpha defensin 1. In addition, global transcript analyses showed significant changes in gene ontology terms relating to immunity and inflammation, however, infiltration of immune and inflammatory cells detected by IHC was unaffected by HRG expression. Conclusion HRG expression by MZL tumor cells correlates with an altered transcription profile and improved overall survival.
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- 2020
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7. A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells
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Amineh Ghaderi, Wen Zhong, Mohammad Ali Okhovat, Johanna Aschan, Ann Svensson, Birgitta Sander, Johan Schultz, Thomas Olin, Anders Österborg, Mohammad Hojjat-Farsangi, and Håkan Mellstedt
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MCL ,ROR1 ,small molecules ,apoptosis ,targeted therapy ,Pharmacy and materia medica ,RS1-441 - Abstract
The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3Kδ/AKT/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL.
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- 2022
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8. Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
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Peter Järver, Aleksandra Dondalska, Candice Poux, AnnSofi Sandberg, Joseph Bergenstråhle, Annette E. Sköld, Nathalie Dereuddre-Bosquet, Fréderic Martinon, Sandra Pålsson, Eman Zaghloul, David Brodin, Birgitta Sander, Kim A. Lennox, Mark A. Behlke, Samir EL-Andaloussi, Janne Lehtiö, Joakim Lundeberg, Roger LeGrand, and Anna-Lena Spetz
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Clathrin-mediated Endocytosis (CME) ,Endosomal TLR ,Endocytic Uptake ,Signaling Endosomes ,Inhibiting TLR4 Activation ,Medicine ,Science - Abstract
Abstract Recognition of nucleic acids by endosomal Toll-like receptors (TLR) is essential to combat pathogens, but requires strict control to limit inflammatory responses. The mechanisms governing this tight regulation are unclear. We found that single-stranded oligonucleotides (ssON) inhibit endocytic pathways used by cargo destined for TLR3/4/7 signaling endosomes. Both ssDNA and ssRNA conferred the endocytic inhibition, it was concentration dependent, and required a certain ssON length. The ssON-mediated inhibition modulated signaling downstream of TLRs that localized within the affected endosomal pathway. We further show that injection of ssON dampens dsRNA-mediated inflammatory responses in the skin of non-human primates. These studies reveal a regulatory role for extracellular ssON in the endocytic uptake of TLR ligands and provide a mechanistic explanation of their immunomodulation. The identified ssON-mediated interference of endocytosis (SOMIE) is a regulatory process that temporarily dampens TLR3/4/7 signaling, thereby averting excessive immune responses.
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- 2018
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9. Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma
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Agata M. Wasik, Chenglin Wu, Larry Mansouri, Richard Rosenquist, Qiang Pan-Hammarström, and Birgitta Sander
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Specialties of internal medicine ,RC581-951 - Published
- 2018
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10. Impact of Sox11 over-expression in Ba/F3 cells
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Martin Lord, Gustav Arvidsson, Agata M. Wasik, Birger Christensson, Anthony P. Wright, Alf Grandien, and Birgitta Sander
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2018
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11. Mixed-species RNAseq analysis of human lymphoma cells adhering to mouse stromal cells identifies a core gene set that is also differentially expressed in the lymph node microenvironment of mantle cell lymphoma and chronic lymphocytic leukemia patients
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Gustav Arvidsson, Johan Henriksson, Birgitta Sander, and Anthony P. Wright
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
A subset of hematologic cancer patients is refractory to treatment or suffers relapse, due in part to minimal residual disease, whereby some cancer cells survive treatment. Cell-adhesion-mediated drug resistance is an important mechanism, whereby cancer cells receive survival signals via interaction with e.g. stromal cells. No genome-wide studies of in vitro systems have yet been performed to compare gene expression in different cell subsets within a co-culture and cells grown separately. Using RNA sequencing and species-specific read mapping, we compared transcript levels in human Jeko-1 mantle cell lymphoma cells stably adhered to mouse MS-5 stromal cells or in suspension within a co-culture or cultured separately as well as in stromal cells in co-culture or in separate culture. From 1050 differentially expressed transcripts in adherent mantle cell lymphoma cells, we identified 24 functional categories that together represent four main functional themes, anti-apoptosis, B-cell signaling, cell adhesion/migration and early mitosis. A comparison with previous mantle cell lymphoma and chronic lymphocytic leukemia studies, of gene expression differences between lymph node and blood, identified 116 genes that are differentially expressed in all three studies. From these genes, we suggest a core set of genes (CCL3, CCL4, DUSP4, ETV5, ICAM1, IL15RA, IL21R, IL4I1, MFSD2A, NFKB1, NFKBIE, SEMA7A, TMEM2) characteristic of cells undergoing cell-adhesion-mediated microenvironment signaling in mantle cell lymphoma/chronic lymphocytic leukemia. The model system developed and characterized here together with the core gene set will be useful for future studies of pathways that mediate increased cancer cell survival and drug resistance mechanisms.
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- 2018
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12. Prognostic relevance of CD163 and CD8 combined with EZH2 and gain of chromosome 18 in follicular lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium
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Wendy B.C. Stevens, Matias Mendeville, Robert Redd, Andrew J. Clear, Reno Bladergroen, Maria Calaminici, Andreas Rosenwald, Eva Hoster, Wolfgang Hiddemann, Philippe Gaulard, Luc Xerri, Gilles Salles, Wolfram Klapper, Michael Pfreundschuh, Andrew Jack, Randy D. Gascoyne, Yasodha Natkunam, Ranjana Advani, Eva Kimby, Birgitta Sander, Laurie H. Sehn, Anton Hagenbeek, John Raemaekers, John Gribben, Marie José Kersten, Bauke Ylstra, Edie Weller, and Daphne de Jong
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In follicular lymphoma, studies addressing the prognostic value of microenvironment-related immunohistochemical markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium performed a validation study evaluating published markers. To maximize sensitivity, an end of spectrum design was applied for 122 uniformly immunochemotherapy-treated follicular lymphoma patients retrieved from international trials and registries. The criteria were: early failure, progression or lymphoma-related death 5 years. Immunohistochemical staining for T cells and macrophages was performed on tissue microarrays from initial biopsies and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. The 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type (P=0.006), gain of chromosome 18 (P=0.002), low percentages of CD8+ cells (P=0.011) and CD163+ areas (P=0.038) were associated with early failure. No significant differences in other markers were observed, thereby refuting previous claims of their prognostic significance. Using an optimized study design, this Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP [-like]), while refuting the prognostic impact of various other markers.
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- 2017
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13. The utility of mRNA analysis in defining SOX11 expression levels in mantle cell lymphoma and reactive lymph nodes
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Martin Lord, Agata M. Wasik, Birger Christensson, and Birgitta Sander
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2015
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14. Influence of rimonabant treatment on peripheral blood mononuclear cells; flow cytometry analysis and gene expression profiling
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Stefan Almestrand, Xiao Wang, Åsa Jeppsson-Ahlberg, Marcus Nordgren, Jenny Flygare, Birger Christensson, Stephan Rössner, and Birgitta Sander
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Blood leukocytes ,Gene expression profiling ,Cannabinoid receptor ,Rimonabant ,Flow cytometry ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
The cannabinoid receptor type 1 (CB1) antagonist rimonabant has been used as treatment for obesity. In addition, anti-proliferative effects on mitogen-activated leukocytes have been demonstrated in vitro. We have previously shown that rimonabant (SR141716A) induces cell death in ex vivo isolated malignant lymphomas with high expression of CB1 receptors. Since CB1 targeting may be part of a future lymphoma therapy, it was of interest to investigate possible effects on peripheral blood mononuclear cells (PBMC) in patients treated with rimonabant. We therefore evaluated leukocyte subsets by 6 color flow cytometry in eight patients before and at treatment with rimonabant for 4 weeks. Whole-transcript gene expression profiling in PBMC before and at 4 weeks of rimonabant treatment was done using Affymetrix Human Gene 1.0 ST Arrays. Our data show no significant changes of monocytes, B cells, total T cells or T cell subsets in PBMC during treatment with rimonabant. There was a small but significant increase in CD3–, CD16+ and/or CD56+ cells after rimonabant therapy. Gene expression analysis detected significant changes in expression of genes associated with innate immunity, cell death and metabolism. The present study shows that normal monocytes and leukocyte subsets in blood remain rather constant during rimonabant treatment. This is in contrast to the induction of cell death previously observed in CB1 expressing lymphoma cells in response to treatment with rimonabant in vitro. These differential effects observed on normal and malignant lymphoid cells warrant investigation of CB1 targeting as a potential lymphoma treatment.
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- 2015
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15. The reliability of immunohistochemical analysis of the tumor microenvironment in follicular lymphoma: a validation study from the Lunenburg Lymphoma Biomarker Consortium
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Birgitta Sander, Daphne de Jong, Andreas Rosenwald, Wanling Xie, Olga Balagué, Maria Calaminici, Joaquim Carreras, Philippe Gaulard, John Gribben, Anton Hagenbeek, Marie José Kersten, Thierry Jo Molina, Abigail Lee, Santiago Montes-Moreno, German Ott, John Raemaekers, Gilles Salles, Laurie Sehn, Christoph Thorns, Björn E. Wahlin, Randy D. Gascoyne, and Edie Weller
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The cellular microenvironment in follicular lymphoma is of biological and clinical importance. Studies on the clinical significance of non-malignant cell populations have generated conflicting results, which may partly be influenced by poor reproducibility in immunohistochemical marker quantification. In this study, the reproducibility of manual scoring and automated microscopy based on a tissue microarray of 25 follicular lymphomas as compared to flow cytometry is evaluated. The agreement between manual scoring and flow cytometry was moderate for CD3, low for CD4, and moderate to high for CD8, with some laboratories scoring closer to the flow cytometry results. Agreement in manual quantification across the 7 laboratories was low to moderate for CD3, CD4, CD8 and FOXP3 frequencies, moderate for CD21, low for MIB1 and CD68, and high for CD10. Manual scoring of the architectural distribution resulted in moderate agreement for CD3, CD4 and CD8, and low agreement for FOXP3 and CD68. Comparing manual scoring to automated microscopy demonstrated that manual scoring increased the variability in the low and high frequency interval with some laboratories showing a better agreement with automated scores. Manual scoring reliably identified rare architectural patterns of T-cell infiltrates. Automated microscopy analyses for T-cell markers by two different instruments were highly reproducible and provided acceptable agreement with flow cytometry. These validation results provide explanations for the heterogeneous findings on the prognostic value of the microenvironment in follicular lymphoma. We recommend a more objective measurement, such as computer-assisted scoring, in future studies of the prognostic impact of microenvironment in follicular lymphoma patients.
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- 2014
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16. Inhibition of the intrinsic but not the extrinsic apoptosis pathway accelerates and drives MYC-driven tumorigenesis towards acute myeloid leukemia.
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Kari Högstrand, Eduar Hejll, Birgitta Sander, Björn Rozell, Lars-Gunnar Larsson, and Alf Grandien
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Medicine ,Science - Abstract
Myc plays an important role in tumor development, including acute myeloid leukemia (AML). However, MYC is also a powerful inducer of apoptosis, which is one of the major failsafe programs to prevent cancer development. To clarify the relative importance of the extrinsic (death receptor-mediated) versus the intrinsic (mitochondrial) pathway of apoptosis in MYC-driven AML, we coexpressed MYC together with anti-apoptotic proteins of relevance for AML; BCL-X(L)/BCL-2 (inhibiting the intrinsic pathway) or FLIP(L) (inhibiting the extrinsic pathway), in hematopoietic stems cells (HSCs). Transplantation of HSCs expressing MYC into syngeneic recipient mice resulted in development of AML and T-cell lymphomas within 7-9 weeks as expected. Importantly, coexpression of MYC together with BCL-X(L)/BCL-2 resulted in strongly accelerated kinetics and favored tumor development towards aggressive AML. In contrast, coexpression of MYC and FLIP(L) did neither accelerate tumorigenesis nor change the ratio of AML versus T-cell lymphoma. However, a change in distribution of immature CD4(+)CD8(+) versus mature CD4(+) T-cell lymphoma was observed in MYC/FLIP(L) mice, possibly as a result of increased survival of the CD4+ population, but this did not significantly affect the outcome of the disease. In conclusion, our findings provide direct evidence that BCL-X(L) and BCL-2 but not FLIP(L) acts in synergy with MYC to drive AML development.
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- 2012
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17. Gene expression profiling and chromatin immunoprecipitation identify DBN1, SETMAR and HIG2 as direct targets of SOX11 in mantle cell lymphoma.
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Xiao Wang, Stefan Björklund, Agata M Wasik, Alf Grandien, Patrik Andersson, Eva Kimby, Karin Dahlman-Wright, Chunyan Zhao, Birger Christensson, and Birgitta Sander
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Medicine ,Science - Abstract
The SRY (sex determining region Y)-box 11 (SOX11) gene, located on chromosome 2p25, encodes for a transcription factor that is involved in tissue remodeling during embryogenesis and is crucial for neurogenesis. The role for SOX11 in hematopoiesis has not yet been defined. Two genes under direct control of SOX11 are the class- III β-tubulin gene (TUBB3) in neural cells and the transcription factor TEA domain family member 2 (TEAD2) in neural and mesenchymal progenitor cells. Normal, mature lymphocytes lack SOX11 but express SOX4, another member of the same group of SOX transcription factors. We and others recently identified SOX11 as aberrantly expressed in mantle cell lymphoma (MCL). Since SOX11 is variably expressed in MCL it may not be essential for tumorigenesis, but may carry prognostic information. Currently, no specific functional effects have been linked to SOX11 expression in MCL and it is not known which genes are under influence of SOX11 in lymphoma. In this study we found variable expression of SOX11, SOX4 and SOX12 mRNA in mantle cell lymphoma cell lines. Downregulation of SOX11 expression by siRNA verified that SOX11 controlled the expression of the gene TUBB3 in the MCL cell line Granta 519. Furthermore we identified, by global gene expression analysis, 26 new target genes influenced by siRNA SOX11 downmodulation. Among these genes, DBN1, SETMAR and HIG2 were found to be significantly correlated to SOX11 expression in two cohorts of primary mantle cell lymphomas. Chromatin immunoprecipitation (ChIP) analysis showed that these genes are direct targets of the SOX11 protein. In spite of almost complete downregulation of the SOX11 protein no significant effects on Granta 519 cell proliferation or survival in short term in vitro experiments was found. In summary we have identified a number of genes influenced by SOX11 expression in MCL cell lines and primary MCL. Among these genes, DBN1, SETMAR and HIG2 are direct transcriptional targets of the SOX11 protein.
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- 2010
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18. Lack of reproducibility of histopathological features in MYC-rearranged large B cell lymphoma using digital whole slide images
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Yasodha Natkunam, Daphne de Jong, Pedro Farinha, Philippe Gaulard, Wolfram Klapper, Andreas Rosenwald, Birgitta Sander, Reuben Tooze, Ranjana Advani, Catherine Burton, John G Gribben, Marie‐José Kersten, Eva Kimby, Georg Lenz, Thierry Molina, Franck Morschhauser, David Scott, Laurie Sehn, Wendy Stevens, Andrew Clear, Maryse Baia, Abdelmalek Habi, Mad‐Helenie Elsensohn, Carole Langlois‐Jacques, Delphine Maucort‐Boulch, Maria Calaminici, Clinical Haematology, AII - Cancer immunology, CCA - Cancer Treatment and Quality of Life, CCA - Cancer biology and immunology, and Pathology
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Histology ,FISH ,MYC-rearrangement ,General Medicine ,high-grade B cell lymphoma ,diffuse large B cell lymphoma ,Pathology and Forensic Medicine ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,digital whole slide image - Abstract
Contains fulltext : 294569.pdf (Publisher’s version ) (Open Access) AIMS: Subclassification of large B cell lymphoma (LBCL) is challenging due to the overlap in histopathological, immunophenotypical and genetic data. In particular, the criteria to separate diffuse large B cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previously reported a cohort of over 5000 LBCL that included fluorescence in-situ hybridisation (FISH) data. This cohort contained 209 cases with MYC rearrangement that were available for a validation study by a panel of eight expert haematopathologists of how various histopathological features are used. METHODS AND RESULTS: Digital whole slide images of haematoxylin and eosin-stained sections allowed the pathologists to visually score cases independently as well as participate in virtual joint review conferences. Standardised consensus guidelines were formulated for scoring histopathological features and included overall architecture/growth pattern, presence or absence of a starry-sky pattern, cell size, nuclear pleomorphism, nucleolar prominence and a range of cytological characteristics. Despite the use of consensus guidelines, the results show a high degree of discordance among the eight expert pathologists. Approximately 50% of the cases lacked a majority score, and this discordance spanned all six histopathological features. Moreover, none of the histological variables aided in prediction of MYC single versus double/triple-hit or immunoglobulin-partner FISH-based designations or clinical outcome measures. CONCLUSIONS: Our findings indicate that there are no specific conventional morphological parameters that help to subclassify MYC-rearranged LBCL or select cases for FISH analysis, and that incorporation of FISH data is essential for accurate classification and prognostication.
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- 2023
19. Chronic lymphocytic leukaemia/small lymphocytic lymphoma and mantle cell lymphoma: from early lesions to transformation
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Birgitta Sander, Elias Campo, and Eric D. Hsi
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Cell Biology ,General Medicine ,Molecular Biology ,Pathology and Forensic Medicine - Abstract
The International Clinical Advisory Committee reviewed advances in our understanding of the clinicopathologic and biologic features of chronic lymphocytic leukaemia/small lymphocytic lymphoma, B-cell prolymphocytic leukaemia, and mantle cell lymphoma since the revised 4th edition of the WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. Discussions amongst pathologists, clinicians, and molecular geneticists around these diseases focussed on incorporating new knowledge into the next classification system. In this manuscript, we review these disease entities and incorporate results of these deliberations, including advances in our understanding of early lesions and transformation.
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- 2022
20. Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV
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G. Tjitske Los-de Vries, Wendy B. C. Stevens, Erik van Dijk, Carole Langois-Jacques, Andrew J. Clear, Phylicia Stathi, Margaretha G. M. Roemer, Matias Mendeville, Nathalie J. Hijmering, Birgitta Sander, Andreas Rosenwald, Maria Calaminici, Eva Hoster, Wolfgang Hiddemann, Philippe Gaulard, Gilles Salles, Heike Horn, Wolfram Klapper, Luc Xerri, Catherine Burton, Reuben M. Tooze, Alexandra G. Smith, Christian Buske, David W. Scott, Yasodha Natkunam, Ranjana Advani, Laurie H. Sehn, John Raemaekers, John Gribben, Eva Kimby, Marie José Kersten, Delphine Maucort-Boulch, Bauke Ylstra, Daphne de Jong, Pathology, CCA - Cancer biology and immunology, and Clinical Haematology
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Histones ,Proto-Oncogene Proteins c-bcl-2 ,Programmed Cell Death 1 Receptor ,Humans ,Hematology ,Genomics ,Lymphoma, Follicular ,Translocation, Genetic ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 282509.pdf (Publisher’s version ) (Open Access) Although the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I cases were analyzed and compared with 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T cells (P = .02) and STAT6 mutations (false discovery rate [FDR]
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- 2022
21. Δ9-THC and CBD in Plasma, Oral Fluid, Exhaled Breath, and Urine from 23 Patients Administered Sativex
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Christopher M. Melén, Magali Merrien, Agata M. Wasik, Birgitta Sander, Björn Engelbrekt Wahlin, Georgios Panagiotis, and Olof Beck
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Pharmacology ,Complementary and alternative medicine ,Pharmacology (medical) - Published
- 2023
22. Supplementary Table 1 from T-Cell Levels Are Prognostic in Mantle Cell Lymphoma
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Birgitta Sander, Björn E. Wahlin, Eva Kimby, Birger Christensson, Daren Buhrkuhl, Patrik Andersson, Monika Klimkowska, Åsa Jeppsson-Ahlberg, Stefanie Baumgartner-Wennerholm, Agata M. Wasik, and Lina Nygren
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Supplementary Table 1. Information regarding the antibody clones used in multiparameter flow cytometry.
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- 2023
23. Supplementary Figure S1 from T-Cell Levels Are Prognostic in Mantle Cell Lymphoma
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Birgitta Sander, Björn E. Wahlin, Eva Kimby, Birger Christensson, Daren Buhrkuhl, Patrik Andersson, Monika Klimkowska, Åsa Jeppsson-Ahlberg, Stefanie Baumgartner-Wennerholm, Agata M. Wasik, and Lina Nygren
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Supplementary Figure S1. Lymphoma cells are visualized by immunohistochemical staining for Cyclin D1. A. Mantle zone subtype is characterized by expanded mantle zones consisting of lymphoma cells which surround preserved germinal centers. B. Nodular subtype C. Diffuse subtype.
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- 2023
24. Supplementary Table 2 from T-Cell Levels Are Prognostic in Mantle Cell Lymphoma
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Birgitta Sander, Björn E. Wahlin, Eva Kimby, Birger Christensson, Daren Buhrkuhl, Patrik Andersson, Monika Klimkowska, Åsa Jeppsson-Ahlberg, Stefanie Baumgartner-Wennerholm, Agata M. Wasik, and Lina Nygren
- Abstract
Supplementary Table 2. T cell levels in diagnostic MCL lymph nodes expressed as median and range of percentage of cells in mononuclear gate.
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- 2023
25. Data from T-Cell Levels Are Prognostic in Mantle Cell Lymphoma
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Birgitta Sander, Björn E. Wahlin, Eva Kimby, Birger Christensson, Daren Buhrkuhl, Patrik Andersson, Monika Klimkowska, Åsa Jeppsson-Ahlberg, Stefanie Baumgartner-Wennerholm, Agata M. Wasik, and Lina Nygren
- Abstract
Purpose: The purpose of this study was to investigate the impact of T-cell subsets on pathologic and clinical features including disease outcome in mantle cell lymphoma (MCL).Experimental Design: Cell populations were investigated using flow cytometry in diagnostic MCL (n = 153) and reactive (n = 26) lymph node biopsies. Levels of tumor cells, T cells, T-cell subsets, and the CD4:CD8 ratio were assessed and related to pathologic and clinical parameters.Results: MCL cases with diffuse and nodular histologic subtypes showed lower levels of T cells, especially CD4+ T cells, than those with mantle zone growth pattern. Both CD3 and CD4 levels were lower in the nodular subtype than in mantle zone (P = 0.007; P = 0.003) and in the diffuse compared with the nodular subtype (P = 0.022; P = 0.015). The CD4:CD8 ratios were inversely correlated to tumor cell proliferation (P = 0.003). Higher levels of CD3+ and CD4+ T cells and higher CD4:CD8 ratios were associated with indolent disease (P = 0.043, 0.021, and 0.003 respectively). In univariate analysis, a high CD4:CD8 ratio, but not the histologic subtype, was correlated to longer overall survival (OS). In multivariate analysis, the CD4:CD8 ratio correlated with OS independently of Mantle Cell Lymphoma International Prognostic Index (MIPI) and high p53 expression (P = 0.023).Conclusion: CD3+, CD8+, and particularly CD4+ T-cell levels are higher in indolent MCL and decrease with more aggressive histology as reflected by a diffuse growth pattern. High CD4:CD8 ratio correlated independently of other high-risk prognostic factors with longer OS, suggesting a prognostic role for T cells in MCL. Clin Cancer Res; 20(23); 6096–104. ©2014 AACR.
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- 2023
26. Data from T Cells in Tumors and Blood Predict Outcome in Follicular Lymphoma Treated with Rituximab
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Eva Kimby, Birger Christensson, Birgitta Sander, Anne M. Tierens, Martin Maisenhölder, Tuula Lehtinen, Peter de Nully Brown, Christian H. Geisler, Bjørn Østenstad, Marie Nordström, Ola Lindén, Herman Nilsson-Ehle, Martin Erlanson, Hans Hagberg, Harald Holte, Christer Sundström, and Björn Engelbrekt Wahlin
- Abstract
Purpose: T cells influence outcome in follicular lymphoma, but their contributions seem to be modified by therapy. Their impact in patients receiving rituximab without chemotherapy is unknown.Experimental Design: Using flow cytometry, we evaluated the T cells in tumors and/or blood in a total of 250 follicular lymphoma patients included in two Nordic Lymphoma Group randomized trials that compared single rituximab with IFN-α2a–rituximab combinations.Results: In univariate analysis, higher levels of CD3+, CD4+, and CD8+ T cells in both tumors and blood correlated with superior treatment responses, and in multivariate analysis, tumor-CD3+ (P = 0.011) and blood-CD4+ (P = 0.029) cells were independent. CD4+ cells were favorable regardless of treatment arm, but CD8+ cells were favorable only in patients treated with single rituximab, because IFN-α2a improved responses especially in patients with low CD8+ cell levels. Higher levels of blood-CD3+ (P = 0.003) and blood-CD4+ (P = 0.046) cells predicted longer overall survival, and higher levels of blood-CD8+ cells longer times to next treatment (P = 0.046).Conclusions: We conclude that therapeutic effects of rituximab are augmented by tumor-associated T cells for rapid responses and by systemic T cells for sustained responses. CD4+ and CD8+ cells are both favorable in patients treated with rituximab. IFN-α2a abrogates the negative impact of few CD8+ cells. Clin Cancer Res; 17(12); 4136–44. ©2011 AACR.
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- 2023
27. Supplementary Materials and Methods from T Cells in Tumors and Blood Predict Outcome in Follicular Lymphoma Treated with Rituximab
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Eva Kimby, Birger Christensson, Birgitta Sander, Anne M. Tierens, Martin Maisenhölder, Tuula Lehtinen, Peter de Nully Brown, Christian H. Geisler, Bjørn Østenstad, Marie Nordström, Ola Lindén, Herman Nilsson-Ehle, Martin Erlanson, Hans Hagberg, Harald Holte, Christer Sundström, and Björn Engelbrekt Wahlin
- Abstract
Supplementary Materials and Methods from T Cells in Tumors and Blood Predict Outcome in Follicular Lymphoma Treated with Rituximab
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- 2023
28. Supplementary Table 4 from Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
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Elías Campo, Sílvia Beà, Kostas Stamatopoulos, Armando Lopez-Guillermo, Reiner Siebert, Eva Giné, Dolors Colomer, Andreas Rosenwald, German Ott, Birgitta Sander, Wendy Erber, Nicola Trim, Maria Jose Calasanz, Christiane Pott, Wyndham Wilson, Adrian Wiestner, Lenka Stefancikova, Alejandra Martinez-Trillos, Virgina Amador, Maria Carmela Vegliante, Jara Palomero, Xavier Puig, Magda Pinyol, Itziar Salaverria, Theodora Papadaki, Nikos Darzentas, Vasilis Bikos, Andreas Agathangelidis, Anastasia Hadzidimitriou, Pedro Jares, Cristina Royo, Guillem Clot, and Alba Navarro
- Abstract
PDF file - 105K, Biological processes and genes differentially expressed among M-MCL (M) and U-MCL (U) validated genes by qPCR
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- 2023
29. Supplementary Table 1 from Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
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Elías Campo, Sílvia Beà, Kostas Stamatopoulos, Armando Lopez-Guillermo, Reiner Siebert, Eva Giné, Dolors Colomer, Andreas Rosenwald, German Ott, Birgitta Sander, Wendy Erber, Nicola Trim, Maria Jose Calasanz, Christiane Pott, Wyndham Wilson, Adrian Wiestner, Lenka Stefancikova, Alejandra Martinez-Trillos, Virgina Amador, Maria Carmela Vegliante, Jara Palomero, Xavier Puig, Magda Pinyol, Itziar Salaverria, Theodora Papadaki, Nikos Darzentas, Vasilis Bikos, Andreas Agathangelidis, Anastasia Hadzidimitriou, Pedro Jares, Cristina Royo, Guillem Clot, and Alba Navarro
- Abstract
PDF file - 105K, Normal B-cell types signatures used in the GSEA analysis
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- 2023
30. Supplementary Figure 3 from Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
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Elías Campo, Sílvia Beà, Kostas Stamatopoulos, Armando Lopez-Guillermo, Reiner Siebert, Eva Giné, Dolors Colomer, Andreas Rosenwald, German Ott, Birgitta Sander, Wendy Erber, Nicola Trim, Maria Jose Calasanz, Christiane Pott, Wyndham Wilson, Adrian Wiestner, Lenka Stefancikova, Alejandra Martinez-Trillos, Virgina Amador, Maria Carmela Vegliante, Jara Palomero, Xavier Puig, Magda Pinyol, Itziar Salaverria, Theodora Papadaki, Nikos Darzentas, Vasilis Bikos, Andreas Agathangelidis, Anastasia Hadzidimitriou, Pedro Jares, Cristina Royo, Guillem Clot, and Alba Navarro
- Abstract
PDF file - 332K, Determination of the best cut-off for the percentage of identity of IGHV gene in relation to overall survival. Two cut-offs, 96.6 and 97%, were selected according to a maximally log-rank statistic
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- 2023
31. Supplementary Table 2 from Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
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Elías Campo, Sílvia Beà, Kostas Stamatopoulos, Armando Lopez-Guillermo, Reiner Siebert, Eva Giné, Dolors Colomer, Andreas Rosenwald, German Ott, Birgitta Sander, Wendy Erber, Nicola Trim, Maria Jose Calasanz, Christiane Pott, Wyndham Wilson, Adrian Wiestner, Lenka Stefancikova, Alejandra Martinez-Trillos, Virgina Amador, Maria Carmela Vegliante, Jara Palomero, Xavier Puig, Magda Pinyol, Itziar Salaverria, Theodora Papadaki, Nikos Darzentas, Vasilis Bikos, Andreas Agathangelidis, Anastasia Hadzidimitriou, Pedro Jares, Cristina Royo, Guillem Clot, and Alba Navarro
- Abstract
PDF file - 75K, IGHV, IGHD and IGHJ gene frequencies according to mutational status
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- 2023
32. Supplementary Table 3 from Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
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Elías Campo, Sílvia Beà, Kostas Stamatopoulos, Armando Lopez-Guillermo, Reiner Siebert, Eva Giné, Dolors Colomer, Andreas Rosenwald, German Ott, Birgitta Sander, Wendy Erber, Nicola Trim, Maria Jose Calasanz, Christiane Pott, Wyndham Wilson, Adrian Wiestner, Lenka Stefancikova, Alejandra Martinez-Trillos, Virgina Amador, Maria Carmela Vegliante, Jara Palomero, Xavier Puig, Magda Pinyol, Itziar Salaverria, Theodora Papadaki, Nikos Darzentas, Vasilis Bikos, Andreas Agathangelidis, Anastasia Hadzidimitriou, Pedro Jares, Cristina Royo, Guillem Clot, and Alba Navarro
- Abstract
PDF file - 108K, P-values of the 518 genes differentially expressed between M-MCL and U-MCL
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- 2023
33. Supplementary Figure 2 from Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
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Elías Campo, Sílvia Beà, Kostas Stamatopoulos, Armando Lopez-Guillermo, Reiner Siebert, Eva Giné, Dolors Colomer, Andreas Rosenwald, German Ott, Birgitta Sander, Wendy Erber, Nicola Trim, Maria Jose Calasanz, Christiane Pott, Wyndham Wilson, Adrian Wiestner, Lenka Stefancikova, Alejandra Martinez-Trillos, Virgina Amador, Maria Carmela Vegliante, Jara Palomero, Xavier Puig, Magda Pinyol, Itziar Salaverria, Theodora Papadaki, Nikos Darzentas, Vasilis Bikos, Andreas Agathangelidis, Anastasia Hadzidimitriou, Pedro Jares, Cristina Royo, Guillem Clot, and Alba Navarro
- Abstract
PDF file - 198K, Recurrent mutations in rearrangements utilizing the six most frequent IGHV genes. Individual codons are represented in the X-axis. Each color represents a different amino acid (AA) change. CDR: complementary determining region, FR: framework region
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- 2023
34. Supplementary Figure 1 from Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
- Author
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Elías Campo, Sílvia Beà, Kostas Stamatopoulos, Armando Lopez-Guillermo, Reiner Siebert, Eva Giné, Dolors Colomer, Andreas Rosenwald, German Ott, Birgitta Sander, Wendy Erber, Nicola Trim, Maria Jose Calasanz, Christiane Pott, Wyndham Wilson, Adrian Wiestner, Lenka Stefancikova, Alejandra Martinez-Trillos, Virgina Amador, Maria Carmela Vegliante, Jara Palomero, Xavier Puig, Magda Pinyol, Itziar Salaverria, Theodora Papadaki, Nikos Darzentas, Vasilis Bikos, Andreas Agathangelidis, Anastasia Hadzidimitriou, Pedro Jares, Cristina Royo, Guillem Clot, and Alba Navarro
- Abstract
PDF file - 73K, SOX11 expression evaluated by three different techniques. One-hundred-sixty-one MCL patients were studied, 64 by immunohistochemistry (IHC), 143 by quantitative PCR (qPCR) and 50 by gene expression profiling (GEP). Several samples were evaluated with more than one technique, and 8 patients were assessed by all three methodologies. The results were concordant in all cases
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- 2023
35. Clinical and biological impact of SAMHD1 expression in mantle cell lymphoma
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Agata M. Wasik, Nikolas Herold, Birger Christensson, Elin Ljung, Arne Kolstad, Georgios Z. Rassidakis, Björn E. Wahlin, Mats Jerkeman, Birgitta Sander, Mattias Carlsten, Mohammad H. A. Morsy, Joana M. Rodrigues, Magali Merrien, and Sara Ek
- Subjects
medicine.medical_specialty ,Chemotherapy ,education.field_of_study ,Hematology ,business.industry ,medicine.medical_treatment ,Population ,Myeloid leukemia ,Cell Biology ,General Medicine ,medicine.disease ,Pathology and Forensic Medicine ,Autologous stem-cell transplantation ,Cell culture ,Internal medicine ,Cytarabine ,Cancer research ,Medicine ,Mantle cell lymphoma ,business ,education ,Molecular Biology ,medicine.drug - Abstract
SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158).
- Published
- 2021
36. Long-Term Follow-up of Clinical Outcome Determinants and Correlative Biological Features from the Nordic NLG-T-01 Trial
- Author
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Thomas Relander, Martin Bjerregård Pedersen, Fredrik Ellin, Grete Fossum Lauritzsen, Esa Jantunen, Hans Hagberg, Harald Holte, Anders Österborg, Peter De Nully Brown, Outi Kuittinen, Martin Erlanson, Bjorn Ostenstad, Unn-Merete Fagerli, Jan Delabie, Christer Sundström, Birgitta Sander, Stephen Hamilton-Dutoit, Mats Ehinger, Knut Liestol, Helle Toldbod, Andrew L. Feldman, and Francesco Annibale d'Amore
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
37. Correction to: Chronic lymphocytic leukaemia/small lymphocytic lymphoma and mantle cell lymphoma: from early lesions to transformation
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Birgitta Sander, Elias Campo, and Eric D. Hsi
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Cell Biology ,General Medicine ,Molecular Biology ,Pathology and Forensic Medicine - Published
- 2023
38. 2-Arachidonoylglycerol Modulates CXCL12-Mediated Chemotaxis in Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia
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Magali Merrien, Agata M. Wasik, Christopher M. Melén, Mohammad Hamdy Abdelrazak Morsy, Kristina Sonnevi, Henna-Riikka Junlén, Birger Christensson, Björn E. Wahlin, and Birgitta Sander
- Subjects
CXCR4 ,Cancer Research ,cannabinoid receptors ,Oncology ,2-arachidonolglycerol ,leukemia ,lymphoma ,chemotaxis - Abstract
To survive chemotherapy, lymphoma cells can relocate to protective niches where they receive support from the non-malignant cells. The biolipid 2-arachidonoylglycerol (2-AG), an agonist for the cannabinoid receptors CB1 and CB2, is released by stromal cells in the bone marrow. To investigate the role of 2-AG in lymphoma, we analyzed the chemotactic response of primary B-cell lymphoma cells enriched from peripheral blood of twenty-two chronic lymphocytic leukemia (CLL) and five mantle cell lymphoma (MCL) patients towards 2-AG alone and/or to the chemokine CXCL12. The expression of cannabinoid receptors was quantified using qPCR and the protein levels visualized by immunofluorescence and Western blot. Surface expression of CXCR4, the main cognate receptor to CXCL12, was analyzed by flow cytometry. Phosphorylation of key downstream signaling pathways activated by 2-AG and CXCL12 were measured by Western blot in three MCL cell lines and two primary CLL samples. We report that 2-AG induces chemotaxis in 80% of the primary samples, as well as 2/3 MCL cell lines. 2-AG induced in a dose-dependent manner, the migration of JeKo-1 cell line via CB1 and CB2. 2-AG affected the CXCL12-mediated chemotaxis without impacting the expression or internalization of CXCR4. We further show that 2-AG modulated p38 and p44/42 MAPK activation. Our results suggest that 2-AG has a previously unrecognized role in the mobilization of lymphoma cells by effecting the CXCL12-induced migration and the CXCR4 signaling pathways, however, with different effects in MCL compared to CLL.
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- 2023
39. Graft‐versus‐mastocytosis effect after donor lymphocyte infusion: Proof of principle
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Arta Dreimane, Akif Selim Yavuz, Claes Malm, Gunnar Nilsson, Hans Hägglund, Birgitta Sander, and Anders Sundin
- Subjects
medicine.medical_specialty ,Lymphocyte ,Case Report ,donor lymphocyte infusion ,Case Reports ,systemic mastocytosis ,graft‐versus‐mastocytosis effect ,graft-versus-mastocytosis effect ,Gastroenterology ,Donor lymphocyte infusion ,03 medical and health sciences ,0302 clinical medicine ,Polycythemia vera ,graft‐ versus‐ mastocytosis effect ,hemic and lymphatic diseases ,Internal medicine ,Urologi och njurmedicin ,medicine ,Urology and Nephrology ,Hematologi ,Systemic mastocytosis ,Myeloproliferative neoplasm ,business.industry ,Myeloid leukemia ,Hematology ,General Medicine ,Mast cell leukemia ,medicine.disease ,Transplantation ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,business ,030215 immunology - Abstract
Advanced systemic mastocytosis is a relatively rare entity where allogeneic stem cell transplantation can lead to the cure of the disease in selected patients. Delayed incomplete responses with graft-versus-mastocytosis effect were published in a few cases. In this particular patients report, we describe the direct evidence and potency of graft-versus-mastocytosis effect of donor lymphocyte infusions in a patient with systemic mastocytosis with associated hematological neoplasm (SM-AHN). In a 53-year-old female patient, an allogeneic stem cell transplantation after conventional induction treatment was performed for transformed acute myeloid leukemia (AML) during the course of polycythemia vera. After 6 years of remission period of AML and PV, the patient developed aleukemic mast cell leukemia and JAK2-positive myeloproliferative neoplasm (SM-AHN). We were able to achieve a sustained complete remission of SM-AHN lasting for 6 years with only donor lymphocyte infusions in a status of mixed chimerism. The patient is in a good clinical condition and remission. The potent graft-versus-mastocytosis effect in this patient resembles the favorable effect of donor lymphocyte infusions in relapsing chronic myeloid leukemia patients after transplantation. This patient is, to our knowledge, the first case showing the proof of principle of graft-versus-mastocytosis effect. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society
- Published
- 2020
40. The extent of residual WT HSPCs is associated with the degree of anemia in patients with SF3B1-mutated MDS-RS
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Isabel Juliana F. Hofman, Teresa Mortera-Blanco, Pedro Luis Moura, Johanna Vestlund, Sigita Venckute Larsson, Edda M. Elvarsdottir, Gunilla Walldin, Magnus Tobiasson, Birgitta Sander, Marios Dimitriou, Sten-Eirik W. Jacobsen, Petter S. Woll, Martin Jädersten, and Eva Hellström-Lindberg
- Subjects
Myelodysplastic Syndromes ,Humans ,Anemia ,Hematology ,RNA Splicing Factors ,Phosphoproteins - Published
- 2022
41. Sting Is Commonly and Differentially Expressed in T- and Nk-Cell but Not B-Cell Non-Hodgkin Lymphomas
- Author
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Rassidakis, Ioanna Xagoraris, Pedro Farrajota Neves da Silva, Georgia Kokaraki, Konstantina Stathopoulou, Björn Wahlin, Anders Österborg, Nikolas Herold, Siok-Bian Ng, L. Jeffrey Medeiros, Elias Drakos, Birgitta Sander, and George Z.
- Subjects
immune system diseases ,hemic and lymphatic diseases ,STING ,T-cell non-Hodgkin lymphoma ,immune response ,eye diseases - Abstract
The expression patterns of stimulator of interferon genes (STING) were investigated in a cohort of 158 T- and natural killer (NK)-cell and 265 B-cell non-Hodgkin lymphomas (NHLs), as well as in control reactive lymph nodes and tonsils. STING expression was assessed by immunohistochemical methods using diagnostic biopsy specimens obtained prior to treatment. Using an arbitrary 10% cutoff, STING was differentially expressed among T/NK-cell NHLs; positive in 36 out of 38 (95%) cases of ALK+ anaplastic large cell lymphoma (ALCL), 23 out of 37 (62%) ALK-ALCLs, 1 out of 13 (7.7%) angioimmunoblastic T-cell lymphomas, 15 out of 19 (79%) peripheral T-cell lymphomas, not otherwise specified, 20 out of 36 (56%) extranodal NK/T-cell lymphomas of nasal type, 6 out of 7 (86%) T-cell lymphoblastic lymphomas, and 3 out of 4 (75%) mycosis fungoides. STING expression did not correlate with clinicopathological parameters or outcome in these patients with T/NK-cell lymphoma. By contrast, all 265 B-cell NHLs of various types were STING-negative. In addition, STING mRNA levels were very high in 6 out of 7 T-cell NHL cell lines, namely, ALK+ and ALK-ALCL cell lines, and very low or undetectable in 7 B-cell NHL cell lines, suggesting transcriptional downregulation of STING in neoplastic B-cells. At the protein level, using Western blot analysis and immunohistochemistry performed on cell blocks, STING expression was found to be restricted to T-cell NHL cell lines. Taken together, STING expression represents a novel biomarker and therapeutic target in T- and NK-cell lymphomas with direct immunotherapeutic implications since modulators of cGAS–STING activity are already available for clinical use.
- Published
- 2022
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42. Marginal zone lymphoma expression of histidine‐rich glycoprotein correlates with improved survival
- Author
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Alex R. Gholiha, Lena Claesson-Welsh, Cecilia Lindskog, Ross O Smith, Ingrid Glimelius, Tor Persson Skare, Gunilla Enblad, Mattias Berglund, Elin Sjöberg, Francis P. Roche, Birgitta Sander, and Rose-Marie Amini
- Subjects
Histidine-rich glycoprotein ,Marginal zone lymphoma ,Gene expression ,Improved survival ,Biology ,Molecular biology - Abstract
The abundant hepatocyte-expressed plasma protein histidine-rich glycoprotein (HRG) enhances antitumor immunity by polarizing inflammatory and immune cells in several mouse models, however, the clinical relevance of HRG in human cancer is poorly explored. The expression and role of HRG in human B-cell lymphomas was investigated in order to find new tools for prognosis and treatment.Immunohistochemical (IHC) analysis and RNA hybridization of tissue microarrays showed that (i) HRG was expressed by tumor cells in marginal zone lymphoma (MZL), in 36% of 59 cases. Expression was also detected in follicular lymphoma (22%), mantle cell lymphoma (19%), and indiffuse large B-cell lymphoma (DLBCL;5%) while primary CNS lymphoma (PCNSL) lacked expression of HRG. (ii) MZL patients positive for HRG showed a superior overall survival outcome (HR = 0.086, 95% CI = 0.014-0.518,HRG expression by MZL tumor cells correlates with an altered transcription profile and improved overall survival.
- Published
- 2020
43. Clinical effects of a single dose of cannabinoids to patients with chronic lymphocytic leukemia
- Author
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Christopher M. Melén, Magali Merrien, Agata M. Wasik, Georgios Panagiotidis, Olof Beck, Kristina Sonnevi, Henna-Riikka Junlén, Birger Christensson, Birgitta Sander, and Björn Engelbrekt Wahlin
- Subjects
Cancer Research ,Oncology ,Cannabinoids ,Cannabidiol ,Humans ,Hematology ,Dronabinol ,Leukemia, Lymphocytic, Chronic, B-Cell - Abstract
This phase II clinical trial investigates a one-time oromucosal dose of tetrahydrocannabinol/cannabidiol (THC/CBD) in 23 patients with indolent leukemic B cell lymphomas. Primary endpoint was a significant reduction in leukemic B cells. Grade 1 - 2 adverse events were seen in 91% of the patients; most common were dry mouth (78%), vertigo (70%), and somnolence (43%). After THC/CBD a significant reduction in leukemic B cells (median, 11%) occurred within two hours (
- Published
- 2022
44. Clinical characteristic and outcome of lymphoplasmacytic lymphoma of non-Waldenstrom macroglobulinemia type : A Swedish lymphoma registry study
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Lena Brandefors, Birgitta Sander, Kristina Lundqvist, and Eva Kimby
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Sweden ,Lymphoma, B-Cell ,Lymphoma ,nutritional and metabolic diseases ,Hematology ,Humans ,lymphoplasmacytic lymphoma ,risk factors ,lipids (amino acids, peptides, and proteins) ,clinical aspects ,epidemiology ,Registries ,Hematologi ,Waldenstrom Macroglobulinemia - Abstract
Lymphoplasmacytic lymphoma (LPL) not fulfilling the WHO diagnostic criteria (2017) for Waldenstrom’s macroglobulinemia (WM) (named non-WM LPL) is a rare disease and only a few systematic studies have been published. Here, we present a population-based study of non-WM LPL focusing on diagnostic difficulties, patient characteristics, and outcome. From 1511 patients included in the Swedish Lymphoma Registry 1 Jan 2000 – 31 Dec 2014 with a diagnosis of WM/LPL, we could confirm the diagnosis of non-WM LP in only 33 patients. The median age at diagnosis was 69 years. A paraprotein was found in most (IgG in 54%, IgA in 15%) and 12% of the cases were non-secretory. Compared with the WM patients, the non-WM LPL patients were younger, had more adverse prognostic factors such as elevated LDH, anaemia, and lymphocytosis at diagnosis. In addition, the non-WM LPL patients more often were symptomatic and received treatment at diagnosis. The overall survival (OS) did not significantly differ between the non-WM LPL and WM groups (P = 0.247), with a median survival time of 71 and 96 months, respectively. To conclude, we found differences in clinical features between WM and non-WM LPL, but no difference in survival.
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- 2022
45. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee
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Elias Campo, Elaine S. Jaffe, James R. Cook, Leticia Quintanilla-Martinez, Steven H. Swerdlow, Kenneth C. Anderson, Pierre Brousset, Lorenzo Cerroni, Laurence de Leval, Stefan Dirnhofer, Ahmet Dogan, Andrew L. Feldman, Falko Fend, Jonathan W. Friedberg, Philippe Gaulard, Paolo Ghia, Steven M. Horwitz, Rebecca L. King, Gilles Salles, Jesus San-Miguel, John F. Seymour, Steven P. Treon, Julie M. Vose, Emanuele Zucca, Ranjana Advani, Stephen Ansell, Wing-Yan Au, Carlos Barrionuevo, Leif Bergsagel, Wing C. Chan, Jeffrey I. Cohen, Francesco d’Amore, Andrew Davies, Brunangelo Falini, Irene M. Ghobrial, John R. Goodlad, John G. Gribben, Eric D. Hsi, Brad S. Kahl, Won-Seog Kim, Shaji Kumar, Ann S. LaCasce, Camille Laurent, Georg Lenz, John P. Leonard, Michael P. Link, Armando Lopez-Guillermo, Maria Victoria Mateos, Elizabeth Macintyre, Ari M. Melnick, Franck Morschhauser, Shigeo Nakamura, Marina Narbaitz, Astrid Pavlovsky, Stefano A. Pileri, Miguel Piris, Barbara Pro, Vincent Rajkumar, Steven T. Rosen, Birgitta Sander, Laurie Sehn, Margaret A. Shipp, Sonali M. Smith, Louis M. Staudt, Catherine Thieblemont, Thomas Tousseyn, Wyndham H. Wilson, Tadashi Yoshino, Pier-Luigi Zinzani, Martin Dreyling, David W. Scott, Jane N. Winter, Andrew D. Zelenetz, Campo E., Jaffe E.S., Cook J.R., Quintanilla-Martinez L., Swerdlow S.H., Anderson K.C., Brousset P., Cerroni L., de Leval L., Dirnhofer S., Dogan A., Feldman A.L., Fend F., Friedberg J.W., Gaulard P., Ghia P., Horwitz S.M., King R.L., Salles G., San-Miguel J., Seymour J.F., Treon S.P., Vose J.M., Zucca E., Advani R., Ansell S., Au W.-Y., Barrionuevo C., Bergsagel L., Chan W.C., Cohen J.I., d'Amore F., Davies A., Falini B., Ghobrial I.M., Goodlad J.R., Gribben J.G., Hsi E.D., Kahl B.S., Kim W.-S., Kumar S., LaCasce A.S., Laurent C., Lenz G., Leonard J.P., Link M.P., Lopez-Guillermo A., Mateos M.V., Macintyre E., Melnick A.M., Morschhauser F., Nakamura S., Narbaitz M., Pavlovsky A., Pileri S.A., Piris M., Pro B., Rajkumar V., Rosen S.T., Sander B., Sehn L., Shipp M.A., Smith S.M., Staudt L.M., Thieblemont C., Tousseyn T., Wilson W.H., Yoshino T., Zinzani P.-L., Dreyling M., Scott D.W., Winter J.N., and Zelenetz A.D.
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Consensus ,Lymphoma ,Hematologic Neoplasms ,Immunology ,Advisory Committees ,Humans ,Cell Biology ,Hematology ,International Consensus Classification, Mature Lymphoid Neoplasms, Clinical Advisory Committee ,World Health Organization ,Biochemistry - Abstract
Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors. ispartof: BLOOD vol:140 issue:11 pages:1229-1253 ispartof: location:United States status: published
- Published
- 2022
46. Sting Is Commonly and Differentially Expressed in T- and Nk-Cell but Not B-Cell Non-Hodgkin Lymphomas
- Author
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Ioanna, Xagoraris, Pedro, Farrajota Neves da Silva, Georgia, Kokaraki, Konstantina, Stathopoulou, Björn, Wahlin, Anders, Österborg, Nikolas, Herold, Siok-Bian, Ng, L Jeffrey, Medeiros, Elias, Drakos, Birgitta, Sander, and George Z, Rassidakis
- Abstract
The expression patterns of stimulator of interferon genes (STING) were investigated in a cohort of 158 T- and natural killer (NK)-cell and 265 B-cell non-Hodgkin lymphomas (NHLs), as well as in control reactive lymph nodes and tonsils. STING expression was assessed by immunohistochemical methods using diagnostic biopsy specimens obtained prior to treatment. Using an arbitrary 10% cutoff, STING was differentially expressed among T/NK-cell NHLs; positive in 36 out of 38 (95%) cases of ALK+ anaplastic large cell lymphoma (ALCL), 23 out of 37 (62%) ALK-ALCLs, 1 out of 13 (7.7%) angioimmunoblastic T-cell lymphomas, 15 out of 19 (79%) peripheral T-cell lymphomas, not otherwise specified, 20 out of 36 (56%) extranodal NK/T-cell lymphomas of nasal type, 6 out of 7 (86%) T-cell lymphoblastic lymphomas, and 3 out of 4 (75%) mycosis fungoides. STING expression did not correlate with clinicopathological parameters or outcome in these patients with T/NK-cell lymphoma. By contrast, all 265 B-cell NHLs of various types were STING-negative. In addition, STING mRNA levels were very high in 6 out of 7 T-cell NHL cell lines, namely, ALK+ and ALK-ALCL cell lines, and very low or undetectable in 7 B-cell NHL cell lines, suggesting transcriptional downregulation of STING in neoplastic B-cells. At the protein level, using Western blot analysis and immunohistochemistry performed on cell blocks, STING expression was found to be restricted to T-cell NHL cell lines. Taken together, STING expression represents a novel biomarker and therapeutic target in T- and NK-cell lymphomas with direct immunotherapeutic implications since modulators of cGAS-STING activity are already available for clinical use.
- Published
- 2021
47. Genomic characterization of lymphomas in patients with inborn errors of immunity
- Author
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Xiaofei, Ye, Paul J, Maglione, Claudia, Wehr, Xiaobo, Li, Yating, Wang, Hassan, Abolhassani, Elena, Deripapa, Dongbing, Liu, Stephan, Borte, Likun, Du, Hui, Wan, Andreas, Plötner, Yvonne, Giannoula, Huai-Bin, Ko, Yong, Hou, Shida, Zhu, Jennifer K, Grossman, Birgitta, Sander, Bodo, Grimbacher, Lennart, Hammarström, Alina, Fedorova, Sergio D, Rosenzweig, Anna, Shcherbina, Kui, Wu, Klaus, Warnatz, Charlotte, Cunningham-Rundles, and Qiang, Pan-Hammarström
- Subjects
Phosphatidylinositol 3-Kinases ,Basic-Leucine Zipper Transcription Factors ,Humans ,Genomics ,Lymphoma, Large B-Cell, Diffuse ,Phosphatidylinositol 3-Kinase - Abstract
Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or -associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified 8 genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase δ syndrome patients. We also identified 5 genomic mutational signatures, including 2 DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy.
- Published
- 2021
48. Clinical and biological impact of SAMHD1 expression in mantle cell lymphoma
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Magali, Merrien, Agata M, Wasik, Elin, Ljung, Mohammad H A, Morsy, Joana, de Matos Rodrigues, Mattias, Carlsten, Georgios Z, Rassidakis, Birger, Christensson, Arne, Kolstad, Mats, Jerkeman, Sara, Ek, Nikolas, Herold, Björn E, Wahlin, and Birgitta, Sander
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Adult ,SAM Domain and HD Domain-Containing Protein 1 ,Antineoplastic Combined Chemotherapy Protocols ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,Humans ,Lymphoma, Mantle-Cell ,Transplantation, Autologous - Abstract
SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158).
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- 2021
49. Real-world data on treatment and outcomes of patients with primary mediastinal large B-cell lymphoma: a Swedish lymphoma register study
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Caroline E. Weibull, Karin E. Smedby, Joel Joelsson, Sverker Hasselblom, Tove Wästerlid, Georgios Rassidakis, and Birgitta Sander
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Epidemiology ,MEDLINE ,Mediastinal Neoplasms ,Young Adult ,Internal medicine ,Correspondence ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Primary Mediastinal Large B-Cell Lymphoma ,B-cell lymphoma ,Register study ,RC254-282 ,Aged ,Aged, 80 and over ,Sweden ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Lymphoma ,Treatment Outcome ,Female ,Lymphoma, Large B-Cell, Diffuse ,business ,Real world data - Published
- 2021
50. A three-dimensional in vitro model of erythropoiesis recapitulates erythroid failure in myelodysplastic syndromes
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Isabel Juliana F Hofman, Mohsen Karimi, Edda María Elvarsdóttir, Petter S. Woll, Thibault Bouderlique, Eva Hellström-Lindberg, Teresa Mortera-Blanco, Iyadh Douagi, Simona Conte, Monika Jansson, Birgitta Sander, and Marios Dimitriou
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0301 basic medicine ,Cancer Research ,Cell Culture Techniques ,CD34 ,Antigens, CD34 ,Anaemia ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,hemic and lymphatic diseases ,medicine ,Humans ,Erythropoiesis ,Cells, Cultured ,Erythroid Precursor Cells ,Myelodysplastic syndromes ,Cell Differentiation ,Mesenchymal Stem Cells ,Hematology ,medicine.disease ,Cell biology ,Haematopoiesis ,030104 developmental biology ,Oncology ,Cell culture ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Regenerative medicine ,Cytokine secretion ,Clone (B-cell biology) - Abstract
Established cell culture systems have failed to accurately recapitulate key features of terminal erythroid maturation, hampering our ability to in vitro model and treat diseases with impaired erythropoiesis such as myelodysplastic syndromes with ring sideroblasts (MDS-RS). We developed an efficient and robust three-dimensional (3D) scaffold culture model supporting terminal erythroid differentiation from both mononuclear (MNC) or CD34+-enriched primary bone marrow cells from healthy donors and MDS-RS patients. While CD34+ cells did not proliferate beyond two weeks in 2D suspension cultures, the 3D scaffolds supported CD34+ and MNC erythroid proliferation over four weeks demonstrating the importance of the 3D environment. CD34+ cells cultured in 3D facilitated the highest expansion and maturation of erythroid cells, including generation of erythroblastic islands and enucleated erythrocytes, while MNCs supported multi-lineage hemopoietic differentiation and cytokine secretion relevant for MDS-RS. Importantly, MDS-RS 3D-cultures supported de novo generation of ring sideroblasts and maintenance of the mutated clone. The 3D cultures effectively model a clonal disease characterized by terminal erythroid failure and can be used to assess therapeutic compounds.
- Published
- 2019
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