25 results on '"De Groen, Ruben A. L."'
Search Results
2. A significant proportion of classic Hodgkin lymphoma recurrences represents clonally unrelated second primary lymphoma
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van Bladel, Diede A. G., Stevens, Wendy B. C., Kroeze, Leonie I., de Groen, Ruben A. L., de Groot, Fleur A., van der Last-Kempkes, Jessica L. M., Berendsen, Madeleine R., Rijntjes, Jos, Luijks, Jeroen A. C. W., Bonzheim, Irina, van der Spek, Ellen, Plattel, Wouter J., Pruijt, Johannes F. M., de Jonge-Peeters, Susan D. P. W. M., Velders, Gerjo A., Lensen, Chantal, van Bladel, Esther R., Federmann, Birgit, Hoevenaars, Brigiet M., Pastorczak, Agata, van der Werff ten Bosch, Jutte, Vermaat, Joost S. P., Nooijen, Peet T. G. A., Hebeda, Konnie M., Fend, Falko, Diepstra, Arjan, van Krieken, J Han J. M., Groenen, Patricia J. T. A., van den Brand, Michiel, and Scheijen, Blanca
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- 2023
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3. Cell-of-origin classification using the Hans and Lymph2Cx algorithms in primary cutaneous large B-cell lymphomas
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Schrader, Anne M. R., de Groen, Ruben A. L., Willemze, Rein, Jansen, Patty M., Quint, Koen D., van Wezel, Tom, van Eijk, Ronald, Ruano, Dina, Tensen, Cornelis P., Hauben, Esther, Woei-A-Jin, F. J. S. H., Busschots, Anne M., van den Berg, Anke, Diepstra, Arjan, Vermeer, Maarten H., and Vermaat, Joost S. P.
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- 2022
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4. The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa
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Vest, Stine Dahl, primary, Eriksen, Patrick Rene Gerhard, additional, de Groot, Fleur A., additional, de Groen, Ruben A. L., additional, Kleij, Anne H. R., additional, Kirkegaard, Marina Knudsen, additional, Kamper, Peter, additional, Rasmussen, Peter Kristian, additional, von Buchwald, Christian, additional, de Nully Brown, Peter, additional, Kiilgaard, Jens Folke, additional, Vermaat, Joost S. P., additional, and Heegaard, Steffen, additional
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- 2024
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5. IGLV3-21*01 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling
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Maity, Palash C., Bilal, Mayas, Koning, Marvyn T., Young, Marc, van Bergen, Cornelis A. M., Renna, Valerio, Nicolò, Antonella, Datta, Moumita, Gentner-Göbel, Eva, Barendse, Rob S., Somers, Sebastiaan F., de Groen, Ruben A. L., Vermaat, Joost S. P., Steinbrecher, Daniela, Schneider, Christof, Tausch, Eugen, Bittolo, Tamara, Bomben, Riccardo, Mazzarello, Andrea Nicola, del Poeta, Giovanni, Kroes, Wilma G. M., van Wezel, J. Tom, Imkeller, Katharina, Busse, Christian E., Degano, Massimo, Bakchoul, Tamam, Schulz, Axel Ronald, Mei, Henrik, Ghia, Paolo, Kotta, Konstantia, Stamatopoulos, Kostas, Wardemann, Hedda, Zucchetto, Antonella, Chiorazzi, Nicholas, Gattei, Valter, Stilgenbauer, Stephan, Veelken, Hendrik, and Jumaa, Hassan
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- 2020
6. Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing
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Arindrarto, Wibowo, Borràs, Daniel M., de Groen, Ruben A. L., van den Berg, Redmar R., Locher, Irene J., van Diessen, Saskia A. M. E., van der Holst, Rosalie, van der Meijden, Edith D., Honders, M. Willy, de Leeuw, Rick H., Verlaat, Wina, Jedema, Inge, Kroes, Wilma G. M., Knijnenburg, Jeroen, van Wezel, Tom, Vermaat, Joost S. P., Valk, Peter J. M., Janssen, Bart, de Knijff, Peter, van Bergen, Cornelis A. M., van den Akker, Erik B., Hoen, Peter A. C. ’t, Kiełbasa, Szymon M., Laros, Jeroen F. J., Griffioen, Marieke, and Veelken, Hendrik
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- 2021
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7. BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis
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Acosta-Medina, Aldo A., primary, Kemps, Paul G., additional, Zondag, Timo C. E., additional, Abeykoon, Jithma P., additional, Forma-Borst, Jelske, additional, Steenwijk, Eline C., additional, Feijen, Elizabeth A. M., additional, Teepen, Jop C., additional, Bennani, N. Nora, additional, Schram, Susan M., additional, Shah, Mithun V., additional, Davidge-Pitts, Caroline, additional, Koster, Matthew J., additional, Ryu, Jay H., additional, Vassallo, Robert, additional, Tobin, W. Oliver, additional, Young, Jason R., additional, Dasari, Surendra, additional, Rech, Karen, additional, Ravindran, Aishwarya, additional, Cleven, Arjen H. G., additional, Verdijk, Robert M., additional, van Noesel, Carel J. M., additional, Balgobind, Brian V., additional, Bouma, Gerrit Joan, additional, Saeed, Peerooz, additional, Bramer, Jos A. M., additional, de Groen, Ruben A. L., additional, Vermaat, Joost S. P., additional, van de Sande, Michiel A. J., additional, Smit, Egbert F., additional, Langerak, Anton W., additional, van Wezel, Tom, additional, Tonino, Sanne H., additional, van den Bos, Cor, additional, van Laar, Jan A. M., additional, Go, Ronald S., additional, Goyal, Gaurav, additional, and van Halteren, Astrid G. S., additional
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- 2023
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8. BRAFV600Eis associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis
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Acosta-Medina, Aldo A., Kemps, Paul G., Zondag, Timo C. E., Abeykoon, Jithma P., Forma-Borst, Jelske, Steenwijk, Eline C., Feijen, Elizabeth A. M., Teepen, Jop C., Bennani, N. Nora, Schram, Susan M., Shah, Mithun V., Davidge-Pitts, Caroline, Koster, Matthew J., Ryu, Jay H., Vassallo, Robert, Tobin, W. Oliver, Young, Jason R., Dasari, Surendra, Rech, Karen, Ravindran, Aishwarya, Cleven, Arjen H. G., Verdijk, Robert M., van Noesel, Carel J. M., Balgobind, Brian V., Bouma, Gerrit Joan, Saeed, Peerooz, Bramer, Jos A. M., de Groen, Ruben A. L., Vermaat, Joost S. P., van de Sande, Michiel A. J., Smit, Egbert F., Langerak, Anton W., van Wezel, Tom, Tonino, Sanne H., van den Bos, Cor, van Laar, Jan A. M., Go, Ronald S., Goyal, Gaurav, and van Halteren, Astrid G. S.
- Abstract
[Display omitted]
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- 2023
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9. Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses: A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring
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Schrader, Anne M. R., primary, de Groen, Ruben A. L., additional, Willemze, Rein, additional, Jansen, Patty M., additional, Quint, Koen D., additional, Cleven, Arjen H. G., additional, van Wezel, Tom, additional, van Eijk, Ronald, additional, Ruano, Dina, additional, Veelken, J. H. (Hendrik), additional, Tensen, Cornelis P., additional, Neelis, Karen J., additional, Daniels, Laurien A., additional, Hauben, Esther, additional, Woei-A-Jin, F. J. S. H. (Sherida), additional, Busschots, A. M. (Annemie), additional, Vermeer, Maarten H., additional, and Vermaat, Joost S. P., additional
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- 2022
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10. BRAFV600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis
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Acosta-Medina, Aldo A., Kemps, Paul G., Zondag, Timo C. E., Abeykoon, Jithma P., Borst, Jelske, Steenwijk, Eline C., Feijen, Elizabeth A. M., Teepen, Jop C., Bennani, N. Nora, Schram, Susan M., Shah, Mithun V., Davidge-Pitts, Caroline, Koster, Matthew J., Ryu, Jay H., Vassallo, Robert, Tobin, W. Oliver, Young, Jason R., Dasari, Surendra, Rech, Karen, Ravindran, Aishwarya, Cleven, Arjen H. G., Verdijk, Robert M., van Noesel, Carel J. M., Balgobind, Brian V., Bouma, Gerrit Joan, Saeed, Peerooz, Bramer, Jos A. M., de Groen, Ruben A. L., Vermaat, Joost S. P., van de Sande, Michiel A. J., Smit, Egbert F., Langerak, Anton W., van Wezel, Tom, Tonino, Sanne H., van den Bos, Cor, van Laar, Jan A. M., Go, Ronald S., Goyal, Gaurav, and van Halteren, Astrid G. S.
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- 2023
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11. Biological and Clinical Implications of Gene-Expression Profiling in Diffuse Large B-Cell Lymphoma: A Proposal for a Targeted BLYM-777 Consortium Panel as Part of a Multilayered Analytical Approach
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Cancer, MS Hematologie, Infection & Immunity, de Groot, Fleur A, de Groen, Ruben A L, van den Berg, Anke, Jansen, Patty M, Lam, King H, Mutsaers, Pim G N J, van Noesel, Carel J M, Chamuleau, Martine E D, Stevens, Wendy B C, Plaça, Jessica R, Mous, Rogier, Kersten, Marie José, van der Poel, Marjolein M W, Tousseyn, Thomas, Woei-A-Jin, F J Sherida H, Diepstra, Arjan, Nijland, Marcel, Vermaat, Joost S P, Cancer, MS Hematologie, Infection & Immunity, de Groot, Fleur A, de Groen, Ruben A L, van den Berg, Anke, Jansen, Patty M, Lam, King H, Mutsaers, Pim G N J, van Noesel, Carel J M, Chamuleau, Martine E D, Stevens, Wendy B C, Plaça, Jessica R, Mous, Rogier, Kersten, Marie José, van der Poel, Marjolein M W, Tousseyn, Thomas, Woei-A-Jin, F J Sherida H, Diepstra, Arjan, Nijland, Marcel, and Vermaat, Joost S P
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- 2022
12. Biological and Clinical Implications of Gene-Expression Profiling in Diffuse Large B-Cell Lymphoma: A Proposal for a Targeted BLYM-777 Consortium Panel as Part of a Multilayered Analytical Approach
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de Groot, Fleur A., primary, de Groen, Ruben A. L., additional, van den Berg, Anke, additional, Jansen, Patty M., additional, Lam, King H., additional, Mutsaers, Pim G. N. J., additional, van Noesel, Carel J. M., additional, Chamuleau, Martine E. D., additional, Stevens, Wendy B. C., additional, Plaça, Jessica R., additional, Mous, Rogier, additional, Kersten, Marie José, additional, van der Poel, Marjolein M. W., additional, Tousseyn, Thomas, additional, Woei-a-Jin, F. J. Sherida H., additional, Diepstra, Arjan, additional, Nijland, Marcel, additional, and Vermaat, Joost S. P., additional
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- 2022
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13. Synchronous diffuse large B-cell lymphoma and mantle cell lymphoma: support for low-threshold biopsies and genetic testing
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de Groot, Fleur A., primary, de Haan, Lorraine M., additional, de Groen, Ruben A. L., additional, Heijmen, Linda, additional, van Wezel, Tom, additional, van Eijk, Ronald, additional, Bohmer, Lara, additional, Bot, Freek, additional, ten Berge, Rosita L., additional, Diepstra, Arjan, additional, Veelken, Hendrik, additional, Cleven, Arjen H. G., additional, Jansen, Patty M., additional, and Vermaat, Joost S. P., additional
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- 2021
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14. Synchronous diffuse large B-cell lymphoma and mantle cell lymphoma: support for low-threshold biopsies and genetic testing.
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de Groot, Fleur A., de Haan, Lorraine M., de Groen, Ruben A. L., Heijmen, Linda, van Wezel, Tom, van Eijk, Ronald, Bohmer, Lara, Bot, Freek, ten Berge, Rosita L., Diepstra, Arjan, Veelken, Hendrik, Cleven, Arjen H. G., Jansen, Patty M., and Vermaat, Joost S. P.
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MANTLE cell lymphoma ,DIFFUSE large B-cell lymphomas ,GENETIC testing ,B cell lymphoma - Abstract
The differential intensity of FDG-avid lesions, along with acute and chronic symptoms and iron deficiency anemia caused by intestine involvement, was suspect for distinct disease entities, and consequently the axilla and colon lesions were biopsied. The intensity PET-CT projection showed multiple lesions with varying maximum standardized uptake values (SUVmax), indicating that these lesions reflect different disease entities (Figure 1(A,B)). These two lesions were biopsied and it has been assumed that these represent all other lesions with comparable FDG-avidity because taking more biopsies is not patient friendly, clinically inefficient and the chances of having a third synchronous lymphoma are negligibly small. The presented unique case demonstrated this individualized approach for both lymphoma subtypes and anatomical sites by adjuvant radiotherapy of the axillary PET avid lesions and the initiation of LR for the persistent MCL bowel lesions. [Extracted from the article]
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- 2022
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15. IGLV3-21*01 is an inherited risk factor for CLL throughthe acquisition of a single-point mutation enablingautonomous BCR signaling
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Maity, Palash C., Bilal, Mayas, Koning, Marvyn T., Young, Marc, Van Bergen, Cornelis A. M., Renna, Valerio, Nicolo, Antonella, Datta, Moumita, Gentner-Göbel, Eva, Barendse, Rob S., Somers, Sebastiaan F., De Groen, Ruben A. L., Vermaat, Joost S. P., Steinbrecher, Daniela, Schneider, Christof, Tausch, Eugen, Bittolo, Tamara, Bomben, Riccardo, Mazzarello, Andrea Nicola, Del Poeta, Giovanni, Kroes, Wilma G. M., Van Wezel, J. Tom, Imkeller, Katharina, Busse, Christian E., Degano, Massimo, Bakchoul, Tamam, Schulz, Axel Ronald, Mei, Henrik, Ghia, Paolo, Kotta, Konstantia, Stamatopoulos, Kostas, Wardemann, Hedda, Zucchetto, Antonella, Chiorazzi, Nicholas, Gattei, Valter, Stilgenbauer, Stephan, Veelken, Hendrik, and Jumaa, Hassan
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GENES ,Survival ,Überleben ,Receptors, Antigen, B-Cell ,Immunoglobulins ,Prognose ,Immunophenotyping ,13Q14 ,DDC 570 / Life sciences ,Antigens, CD ,ddc:570 ,chronic lymphocytic leukemia (CLL) ,LENGTH ,ddc:610 ,PROGNOSTIC INDEX ,immunoglobulin allele IGLV3-21*01 ,autonomous BCR signaling ,Immunogenetic phenomena ,Prognosis ,B-Lymphozyten-Rezeptor ,Leukemia, Lymphocytic, Chronic, B-Cell ,DELETIONS ,Antigen CD38 ,CD38 EXPRESSION ,IMMUNOGLOBULIN HEAVY ,Immunglobuline ,Chronisch-lymphatische Leukämie ,B cell antigen receptor (BCR) ,DDC 610 / Medicine & health - Abstract
The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21–derived heavy chains (HCs) with IGLV3-21–derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21R110), we show that IGLV3-21R110–expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21*01 facilitates effective homotypic BCR–BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21*01–expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21R110–expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors., publishedVersion
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- 2020
16. Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing
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Arindrarto, Wibowo, primary, Borràs, Daniel M., additional, de Groen, Ruben A. L., additional, van den Berg, Redmar R., additional, Locher, Irene J., additional, van Diessen, Saskia A. M. E., additional, van der Holst, Rosalie, additional, van der Meijden, Edith D., additional, Honders, M. Willy, additional, de Leeuw, Rick H., additional, Verlaat, Wina, additional, Jedema, Inge, additional, Kroes, Wilma G. M., additional, Knijnenburg, Jeroen, additional, van Wezel, Tom, additional, Vermaat, Joost S. P., additional, Valk, Peter J. M., additional, Janssen, Bart, additional, de Knijff, Peter, additional, van Bergen, Cornelis A. M., additional, van den Akker, Erik B., additional, Hoen, Peter A. C. ’t, additional, Kiełbasa, Szymon M., additional, Laros, Jeroen F. J., additional, Griffioen, Marieke, additional, and Veelken, Hendrik, additional
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- 2020
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17. IGLV3-21 * 01is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling
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Maity, Palash C., primary, Bilal, Mayas, additional, Koning, Marvyn T., additional, Young, Marc, additional, van Bergen, Cornelis A. M., additional, Renna, Valerio, additional, Nicolò, Antonella, additional, Datta, Moumita, additional, Gentner-Göbel, Eva, additional, Barendse, Rob S., additional, Somers, Sebastiaan F., additional, de Groen, Ruben A. L., additional, Vermaat, Joost S. P., additional, Steinbrecher, Daniela, additional, Schneider, Christof, additional, Tausch, Eugen, additional, Bittolo, Tamara, additional, Bomben, Riccardo, additional, Mazzarello, Andrea Nicola, additional, del Poeta, Giovanni, additional, Kroes, Wilma G. M., additional, van Wezel, J. Tom, additional, Imkeller, Katharina, additional, Busse, Christian E., additional, Degano, Massimo, additional, Bakchoul, Tamam, additional, Schulz, Axel Ronald, additional, Mei, Henrik, additional, Ghia, Paolo, additional, Kotta, Konstantia, additional, Stamatopoulos, Kostas, additional, Wardemann, Hedda, additional, Zucchetto, Antonella, additional, Chiorazzi, Nicholas, additional, Gattei, Valter, additional, Stilgenbauer, Stephan, additional, Veelken, Hendrik, additional, and Jumaa, Hassan, additional
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- 2020
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18. High frequency of inactivating tetraspanin CD37 mutations in diffuse large B-cell lymphoma at immune-privileged sites
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Elfrink, Suraya, primary, de Winde, Charlotte M., additional, van den Brand, Michiel, additional, Berendsen, Madeleine, additional, Roemer, Margaretha G. M., additional, Arnold, Frank, additional, Janssen, Luuk, additional, van der Schaaf, Alie, additional, Jansen, Erik, additional, Groenen, Patricia J. T. A., additional, Eijkelenboom, Astrid, additional, Stevens, Wendy, additional, Hess, Corine J., additional, van Krieken, J. Han, additional, Vermaat, Joost S. P., additional, Cleven, Arjen H. G., additional, de Groen, Ruben A. L., additional, Neviani, Viviana, additional, de Jong, Daphne, additional, van Deventer, Sjoerd, additional, Scheijen, Blanca, additional, and van Spriel, Annemiek B., additional
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- 2019
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19. Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL.
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Eken JA, Koning MT, Kupcova K, Sepúlveda Yáñez JH, de Groen RAL, Quinten E, Janssen J, van Bergen CAM, Vermaat JSP, Cleven A, Navarrete MA, Ylstra B, de Jong D, Havranek O, Jumaa H, and Veelken H
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- Animals, Mice, B-Lymphocytes, Receptors, Antigen, B-Cell, Immunoglobulin M, Lymphoma, Large B-Cell, Diffuse genetics, Leukemia, Lymphocytic, Chronic, B-Cell
- Abstract
Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications., (© 2024 Eken et al.)
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- 2024
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20. Autonomous B-cell receptor signaling and genetic aberrations in chronic lymphocytic leukemia-phenotype monoclonal B lymphocytosis in siblings of patients with chronic lymphocytic leukemia.
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Quinten E, Sepúlveda-Yáñez JH, Koning MT, Eken JA, Pfeifer D, Nteleah V, De Groen RAL, Saravia DA, Knijnenburg J, Stuivenberg-Bleijswijk HE, Pantic M, Agathangelidis A, Keppler-Hafkemeyer A, Van Bergen CAM, Uribe-Paredes R, Stamatopoulos K, Vermaat JSP, Zirlik K, Navarrete MA, Jumaa H, and Veelken H
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- Humans, Animals, Mice, Siblings, DNA Copy Number Variations, Receptors, Antigen, B-Cell genetics, Phenotype, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphocytosis genetics, Leukemia
- Abstract
Clonal expansion of CD5-expressing B cells, commonly designated as monoclonal B lymphocytosis (MBL), is a precursor condition for chronic lymphocytic leukemia (CLL). The mechanisms driving subclinical MBL B-cell expansion and progression to CLL, occurring in approximately 1% of affected individuals, are unknown. An autonomously signaling B-cell receptor (BCR) is essential for the pathogenesis of CLL. The objectives of this study were functional characterization of the BCR of MBL in siblings of CLL patients and a comparison of genetic variants in MBL-CLL sibling pairs. Screening of peripheral blood by flow cytometry detected 0.2-480 clonal CLL-phenotype cells per microliter (median: 37/μL) in 34 of 191 (17.8%) siblings of CLL patients. Clonal BCR isolated from highly purified CLL-phenotype cells induced robust calcium mobilization in BCR-deficient murine pre-B cells in the absence of external antigen and without experimental crosslinking. This autonomous BCR signal was less intense than the signal originating from the CLL BCR of their CLL siblings. According to genotyping by single nucleotide polymorphism array, whole exome, and targeted panel sequencing, CLL risk alleles were found with high and similar prevalence in CLL patients and MBL siblings, respectively. Likewise, the prevalence of recurrent CLL-associated genetic variants was similar between CLL and matched MBL samples. However, copy number variations and small variants were frequently subclonal in MBL cells, suggesting their acquisition during subclinical clonal expansion. These findings support a stepwise model of CLL pathogenesis, in which autonomous BCR signaling leads to a non-malignant (oligo)clonal expansion of CD5+ B cells, followed by malignant progression to CLL after acquisition of pathogenic genetic variants.
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- 2024
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21. Frequent mutated B2M, EZH2, IRF8, and TNFRSF14 in primary bone diffuse large B-cell lymphoma reflect a GCB phenotype.
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de Groen RAL, van Eijk R, Böhringer S, van Wezel T, Raghoo R, Ruano D, Jansen PM, Briaire-de Bruijn I, de Groot FA, Kleiverda K, Te Boome L, Terpstra V, Levenga H, Nicolae A, Posthuma EFM, Focke-Snieders I, Hardi L, den Hartog WCE, Bohmer LH, Hogendoorn PCW, van den Berg A, Diepstra A, Nijland M, Lugtenburg PJ, Kersten MJ, Pals ST, Veelken H, Bovée JVMG, Cleven AHG, and Vermaat JSP
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- Enhancer of Zeste Homolog 2 Protein genetics, Germinal Center metabolism, Humans, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Phenotype, Receptors, Tumor Necrosis Factor, Member 14, Retrospective Studies, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCL with osseous localizations (O-DLBCL), including PB-DLBCL. A total of 103 patients with O-DLBCL were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin was determined by immunohistochemistry and gene-expression profiling (GEP) using (extended)-NanoString/Lymph2Cx analysis. Mutational profiles were identified with targeted next-generation deep sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCLs, were predominantly classified as GCB phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx revealed significantly different GEP clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P < .001). Expression levels of 23 genes of 2 different targeted GEP panels indicated a centrocyte-like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB exhibited a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes (ie, B2M, EZH2, IRF8, TNFRSF14) compared with NO-DLBCL-GCB (P = .031, P = .010, P = .047, and P = .003, respectively). PB-DLBCL, with its corresponding specific mutational profile, was significantly associated with a superior survival compared with equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P = .016). This study is the first to show that PB-DLBCL is characterized by a GCB phenotype, with a centrocyte-like GEP pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity, and its specific mutational landscape offers potential for targeted therapies (eg, EZH2 inhibitors)., (© 2021 by The American Society of Hematology.)
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- 2021
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22. IGLV3-21 * 01 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling.
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Maity PC, Bilal M, Koning MT, Young M, van Bergen CAM, Renna V, Nicolò A, Datta M, Gentner-Göbel E, Barendse RS, Somers SF, de Groen RAL, Vermaat JSP, Steinbrecher D, Schneider C, Tausch E, Bittolo T, Bomben R, Mazzarello AN, Del Poeta G, Kroes WGM, van Wezel JT, Imkeller K, Busse CE, Degano M, Bakchoul T, Schulz AR, Mei H, Ghia P, Kotta K, Stamatopoulos K, Wardemann H, Zucchetto A, Chiorazzi N, Gattei V, Stilgenbauer S, Veelken H, and Jumaa H
- Subjects
- B-Lymphocytes immunology, Cohort Studies, Complementarity Determining Regions genetics, Complementarity Determining Regions immunology, Genetic Predisposition to Disease, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains immunology, Immunoglobulin lambda-Chains immunology, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Point Mutation, Receptors, Antigen, B-Cell genetics, Immunoglobulin lambda-Chains genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Receptors, Antigen, B-Cell immunology
- Abstract
The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21-derived heavy chains (HCs) with IGLV3-21-derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21
R110 ), we show that IGLV3-21R110 -expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21 * 01 facilitates effective homotypic BCR-BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21 * 01 -expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21R110 -expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors., Competing Interests: Competing interest statement: H.J. is a cofounder of AVA LifeScience GmbH that has filed patents on antibodies recognizing structures involved in autonomous BCR signaling., (Copyright © 2020 the Author(s). Published by PNAS.)- Published
- 2020
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23. MYD88 mutations identify a molecular subgroup of diffuse large B-cell lymphoma with an unfavorable prognosis.
- Author
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Vermaat JS, Somers SF, de Wreede LC, Kraan W, de Groen RAL, Schrader AMR, Kerver ED, Scheepstra CG, Berenschot H, Deenik W, Wegman J, Broers R, de Boer JD, Nijland M, van Wezel T, Veelken H, Spaargaren M, Cleven AH, Kersten MJ, and Pals ST
- Subjects
- Herpesvirus 4, Human, Humans, In Situ Hybridization, Fluorescence, Mutation, Prognosis, Epstein-Barr Virus Infections genetics, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse genetics, Myeloid Differentiation Factor 88 genetics
- Abstract
The 2016 World Health Organization classification defines diffuse large B-cell lymphoma (DLBCL) subtypes based on Epstein-Barr virus (EBV) infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis. A subset of DLBCL, however, is characterized by activating mutations in MYD88/CD79B We investigated whether MYD88/CD79B mutations could improve the classification and prognostication of DLBCL. In 250 primary DLBCL, MYD88/CD79B mutations were identified by allele-specific polymerase chain reaction or next-generation-sequencing, MYC/BCL2/BCL6 rearrangements were analyzed by fluorescence in situ hybridization, and EBV was studied by EBV-encoded RNA in situ hybridization. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to the International Prognostic Index (IPI) were investigated. MYD88 and CD79B mutations were identified in 29.6% and 12.3%, MYC, BCL2 , and BCL6 rearrangements in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, and MYD88/CD79B mutations established the value of molecular markers for the recognition of biologically distinct DLBCL subtypes. MYD88 -mutated DLBCL had a significantly inferior 5-year overall survival than wild-type MYD88 DLBCL (log-rank; P =0.019). DLBCL without any of the studied aberrations had superior overall survival compared to cases carrying ≥1 aberrancy (log-rank; P =0.010). MYD88 mutations retained their adverse prognostic impact upon adjustment for other genetic and clinical variables by multivariable analysis and improved the prognostic performance of the IPI. This study demonstrates the clinical utility of defining MYD88 -mutated DLBCL as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of MYD88 in routine diagnostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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24. MYD88 in the driver's seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications.
- Author
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de Groen RAL, Schrader AMR, Kersten MJ, Pals ST, and Vermaat JSP
- Subjects
- Humans, Leukemia, B-Cell genetics, Leukemia, B-Cell metabolism, Lymphoma, B-Cell genetics, Lymphoma, B-Cell metabolism, Prognosis, Gene Expression Regulation, Neoplastic, Leukemia, B-Cell pathology, Lymphoma, B-Cell pathology, Mutation, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism
- Abstract
More than 50 subtypes of B-cell non-Hodgkin lymphoma (B-NHL) are recognized in the most recent World Health Organization classification of 2016. The current treatment paradigm, however, is largely based on 'one-size-fits-all' immune-chemotherapy. Unfortunately, this therapeutic strategy is inadequate for a significant number of patients. As such, there is an indisputable need for novel, preferably targeted, therapies based on a biologically driven classification and risk stratification. Sequencing studies identified mutations in the MYD88 gene as an important oncogenic driver in B-cell lymphomas. MYD88 mutations constitutively activate NF-κB and its associated signaling pathways, thereby promoting B-cell proliferation and survival. High frequencies of the hotspot MYD88 (L265P) mutation are observed in extranodal diffuse large B-cell lymphoma and Waldenström macroglobulinemia, thereby demonstrating this mutation's potential as a disease marker. In addition, the presence of mutant MYD88 predicts survival outcome in B-NHL subtypes and it provides a therapeutic target. Early clinical trials targeting MYD88 have shown encouraging results in relapsed/refractory B-NHL. Patients with these disorders can benefit from analysis for the MYD88 hotspot mutation in liquid biopsies, as a minimally invasive method to demonstrate treatment response or resistance. Given these clear clinical implications and the crucial role of MYD88 in lymphomagenesis, we expect that analysis of this gene will increasingly be used in routine clinical practice, not only as a diagnostic classifier, but also as a prognostic and therapeutic biomarker directing precision medicine. This review focuses on the pivotal mechanistic role of mutated MYD88 and its clinical implications in B-NHL., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
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25. High frequency of inactivating tetraspanin C D37 mutations in diffuse large B-cell lymphoma at immune-privileged sites.
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Elfrink S, de Winde CM, van den Brand M, Berendsen M, Roemer MGM, Arnold F, Janssen L, van der Schaaf A, Jansen E, Groenen PJTA, Eijkelenboom A, Stevens W, Hess CJ, van Krieken JH, Vermaat JSP, Cleven AHG, de Groen RAL, Neviani V, de Jong D, van Deventer S, Scheijen B, and van Spriel AB
- Subjects
- Antigens, Neoplasm chemistry, Antigens, Neoplasm immunology, Central Nervous System immunology, Central Nervous System pathology, Central Nervous System Neoplasms genetics, Central Nervous System Neoplasms immunology, Central Nervous System Neoplasms pathology, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Gene Silencing, Humans, Lymphoma, Large B-Cell, Diffuse epidemiology, Lymphoma, Large B-Cell, Diffuse pathology, Male, Mutation, Testicular Neoplasms genetics, Testicular Neoplasms immunology, Testicular Neoplasms pathology, Testis immunology, Testis pathology, Tetraspanins chemistry, Tetraspanins immunology, Tumor Escape genetics, Tumor Escape immunology, Antigens, Neoplasm genetics, Immune Privilege genetics, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse immunology, Tetraspanins genetics
- Abstract
Tetraspanin CD37 is predominantly expressed on the cell surface of mature B lymphocytes and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated that loss of CD37 induces spontaneous B-cell lymphoma in Cd37 -knockout mice and correlates with inferior survival in patients with diffuse large B-cell lymphoma (DLBCL). Here, CD37 mutation analysis was performed in a cohort of 137 primary DLBCL samples, including 44 primary immune-privileged site-associated DLBCL (IP-DLBCL) samples originating in the testis or central nervous system. CD37 mutations were exclusively identified in IP-DLBCL cases (10/44, 23%) but absent in non-IP-DLBCL cases. The aberrations included 10 missense mutations, 1 deletion, and 3 splice-site CD37 mutations. Modeling and functional analysis of CD37 missense mutations revealed loss of function by impaired CD37 protein expression at the plasma membrane of human lymphoma B cells. This study provides novel insight into the molecular pathogenesis of IP-DLBCL and indicates that anti-CD37 therapies will be more beneficial for DLBCL patients without CD37 mutations., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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