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1. Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer

Author

Arends, Christopher Maximilian, Kopp, Klara, Hablesreiter, Raphael, Estrada, Natalia, Christen, Friederike, Moll, Ute Martha, Zeillinger, Robert, Schmitt, Wolfgang Daniel, Sehouli, Jalid, Kulbe, Hagen, Fleischmann, Maximilian, Ray-Coquard, Isabelle, Zeimet, Alain, Raspagliesi, Francesco, Zamagni, Claudio, Vergote, Ignace, Lorusso, Domenica, Concin, Nicole, Bullinger, Lars, Braicu, Elena Ioana, and Damm, Frederik

Published
2024
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2. Frequent ZNF217 mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma

Author

Briest, Franziska, Noerenberg, Daniel, Hennch, Cornelius, Yoshida, Kenichi, Hablesreiter, Raphael, Nimo, Jose, Sasca, Daniel, Kirchner, Marieluise, Mansouri, Larry, Inoue, Yoshikage, Wiegand, Laura, Staiger, Annette M., Casadei, Beatrice, Korkolopoulou, Penelope, Weiner, January, Lopez-Guillermo, Armando, Warth, Arne, Schneider, Tamás, Nagy, Ákos, Klapper, Wolfram, Hummel, Michael, Kanellis, George, Anagnostopoulos, Ioannis, Mertins, Philipp, Bullinger, Lars, Rosenquist, Richard, Vassilakopoulos, Theodoros P., Ott, German, Ogawa, Seishi, and Damm, Frederik

Published
2023
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3. Correction: Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer

Author

Arends, Christopher Maximilian, Kopp, Klara, Hablesreiter, Raphael, Estrada, Natalia, Christen, Friederike, Moll, Ute Martha, Zeillinger, Robert, Schmitt, Wolfgang Daniel, Sehouli, Jalid, Kulbe, Hagen, Fleischmann, Maximilian, Ray-Coquard, Isabelle, Zeimet, Alain, Raspagliesi, Francesco, Zamagni, Claudio, Vergote, Ignace, Lorusso, Domenica, Concin, Nicole, Bullinger, Lars, Braicu, Elena Ioana, and Damm, Frederik

Published
2024
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4. Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke

Author

Arends, Christopher M., Liman, Thomas G., Strzelecka, Paulina M., Kufner, Anna, Löwe, Pelle, Huo, Shufan, Stein, Catarina M., Piper, Sophie K., Tilgner, Marlon, Sperber, Pia S., Dimitriou, Savvina, Heuschmann, Peter U., Hablesreiter, Raphael, Harms, Christoph, Bullinger, Lars, Weber, Joachim E., Endres, Matthias, and Damm, Frederik

Published
2023
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6. Genetic Characterization of Primary Mediastinal B-Cell Lymphoma : Pathogenesis and Patient Outcomes

Author

Noerenberg, Daniel, Briest, Franziska, Hennch, Cornelius, Yoshida, Kenichi, Hablesreiter, Raphael, Takeuchi, Yasuhide, Ueno, Hiroo, Staiger, Annette M., Ziepert, Marita, Asmar, Fazila, Locher, Benjamin N., Toth, Erika, Weber, Thomas, Amini, Rose-Marie, Klapper, Wolfram, Bouzani, Maria, Poeschel, Viola, Rosenwald, Andreas, Held, Gerhard, Campo, Elias, Ishaque, Naveed, Stamatopoulos, Kostas, Kanellis, George, Anagnostopoulos, Ioannis, Bullinger, Lars, Goldschmidt, Neta, Zinzani, Pier Luigi, Bödör, Csaba, Rosenquist, Richard, Vassilakopoulos, Theodoros P., Ott, German, Ogawa, Seishi, Damm, Frederik, Noerenberg, Daniel, Briest, Franziska, Hennch, Cornelius, Yoshida, Kenichi, Hablesreiter, Raphael, Takeuchi, Yasuhide, Ueno, Hiroo, Staiger, Annette M., Ziepert, Marita, Asmar, Fazila, Locher, Benjamin N., Toth, Erika, Weber, Thomas, Amini, Rose-Marie, Klapper, Wolfram, Bouzani, Maria, Poeschel, Viola, Rosenwald, Andreas, Held, Gerhard, Campo, Elias, Ishaque, Naveed, Stamatopoulos, Kostas, Kanellis, George, Anagnostopoulos, Ioannis, Bullinger, Lars, Goldschmidt, Neta, Zinzani, Pier Luigi, Bödör, Csaba, Rosenquist, Richard, Vassilakopoulos, Theodoros P., Ott, German, Ogawa, Seishi, and Damm, Frederik

Abstract

Purpose Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk stratification are lacking. Patients and Methods To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions. Results Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in TP53-related genes (TP63, TP73, and WWOX) and identified novel SVs facilitating immune evasion (DOCK8 and CD83). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg, ARID1A, P2RY8, and PLXNC1) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact. CD58 mutations (31%) showed the strongest association with worse PFS (hazard ratio [HR], 2.52 [95% CI, 1.50 to 4.21]; P < .001) and overall survival (HR, 2.33 [95% CI, 1.14 to 4.76]; P = .02). IPI high-risk patients with mutated CD58 demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the CD58 mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast, DUSP2-mutated patients (24%) displayed durable responses (PFS: HR, 0.2 [95% CI, 0.07 to 0.55]; P = .002) and prolonged OS (HR, 0.11 [95% CI, 0.01 to 0.78]; P = .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS

Published
2024
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7. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients

Author

Christen, Friederike, Hoyer, Kaja, Yoshida, Kenichi, Hou, Hsin-An, Waldhueter, Nils, Heuser, Michael, Hills, Robert K., Chan, Willy, Hablesreiter, Raphael, Blau, Olga, Ochi, Yotaro, Klement, Piroska, Chou, Wen-Chien, Blau, Igor-Wolfgang, Tang, Jih-Luh, Zemojtel, Tomasz, Shiraishi, Yuichi, Shiozawa, Yusuke, Thol, Felicitas, Ganser, Arnold, Löwenberg, Bob, Linch, David C., Bullinger, Lars, Valk, Peter J.M., Tien, Hwei-Fang, Gale, Rosemary E., Ogawa, Seishi, and Damm, Frederik

Published
2019
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8. Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes

Author

Noerenberg, Daniel, primary, Briest, Franziska, additional, Hennch, Cornelius, additional, Yoshida, Kenichi, additional, Hablesreiter, Raphael, additional, Takeuchi, Yasuhide, additional, Ueno, Hiroo, additional, Staiger, Annette M., additional, Ziepert, Marita, additional, Asmar, Fazila, additional, Locher, Benjamin N., additional, Toth, Erika, additional, Weber, Thomas, additional, Amini, Rose-Marie, additional, Klapper, Wolfram, additional, Bouzani, Maria, additional, Poeschel, Viola, additional, Rosenwald, Andreas, additional, Held, Gerhard, additional, Campo, Elías, additional, Ishaque, Naveed, additional, Stamatopoulos, Kostas, additional, Kanellis, George, additional, Anagnostopoulos, Ioannis, additional, Bullinger, Lars, additional, Goldschmidt, Neta, additional, Zinzani, Pier Luigi, additional, Bödör, Csaba, additional, Rosenquist, Richard, additional, Vassilakopoulos, Theodoros P., additional, Ott, German, additional, Ogawa, Seishi, additional, and Damm, Frederik, additional

Published
2023
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9. Associations of clonal haematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke

Author

Arends, Christopher Maximilian, primary, Liman, Thomas G., additional, Strzelecka, Paulina M, additional, Kufner, Anna, additional, Löwe, Pelle, additional, Huo, Shufan, additional, Stein, Catarina M, additional, Piper, Sophie K., additional, Tilgner, Marlon, additional, Sperber, Pia S., additional, Dimitriou, Savvina, additional, Heuschmann, Peter, additional, Hablesreiter, Raphael, additional, Harms, Christoph, additional, Bullinger, Lars, additional, Weber, Joachim E., additional, Endres, Matthias, additional, and Damm, Frederik, additional

Published
2022
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11. Frequent ZNF217mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma

Author

Briest, Franziska, Noerenberg, Daniel, Hennch, Cornelius, Yoshida, Kenichi, Hablesreiter, Raphael, Nimo, Jose, Sasca, Daniel, Kirchner, Marieluise, Mansouri, Larry, Inoue, Yoshikage, Wiegand, Laura, Staiger, Annette M., Casadei, Beatrice, Korkolopoulou, Penelope, Weiner, January, Lopez-Guillermo, Armando, Warth, Arne, Schneider, Tamás, Nagy, Ákos, Klapper, Wolfram, Hummel, Michael, Kanellis, George, Anagnostopoulos, Ioannis, Mertins, Philipp, Bullinger, Lars, Rosenquist, Richard, Vassilakopoulos, Theodoros P., Ott, German, Ogawa, Seishi, and Damm, Frederik

Abstract

Recent exome-wide studies discovered frequent somatic mutations in the epigenetic modifier ZNF217in primary mediastinal B cell lymphoma (PMBCL) and related disorders. As functional consequences of ZNF217alterations remain unknown, we comprehensively evaluated their impact in PMBCL. Targeted sequencing identified genetic lesions affecting ZNF217in 33% of 157 PMBCL patients. Subsequent gene expression profiling (n= 120) revealed changes in cytokine and interferon signal transduction in ZNF217-aberrant PMBCL cases. In vitro, knockout of ZNF217led to changes in chromatin accessibility interfering with binding motifs for crucial lymphoma-associated transcription factors. This led to disturbed expression of interferon-responsive and inflammation-associated genes, altered cell behavior, and aberrant differentiation. Mass spectrometry demonstrates that ZNF217 acts within a histone modifier complex containing LSD1, CoREST and HDAC and interferes with H3K4 methylation and H3K27 acetylation. Concluding, our data suggest non-catalytic activity of ZNF217, which directs histone modifier complex function and controls B cell differentiation-associated patterns of chromatin structure.

Published
2023
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12. Modeling clonal hematopoiesis in umbilical cord blood cells by CRISPR/Cas9

Author

Christen, Friederike, primary, Hablesreiter, Raphael, additional, Hoyer, Kaja, additional, Hennch, Cornelius, additional, Maluck-Böttcher, Antje, additional, Segler, Angela, additional, Madadi, Annett, additional, Frick, Mareike, additional, Bullinger, Lars, additional, Briest, Franziska, additional, and Damm, Frederik, additional

Published
2021
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13. Clonal Hematopoiesis in Whole-Blood and Cell-Free DNA of Ovarian Cancer Patients Undergoing PARP-Inhibitor Treatment: An Exploratory Analysis of the ENGOT-ov48/Eudario Trial

Author

Arends, Christopher Maximilian, Kopp, Klara, Estrada-Barreras, Natalia, Hablesreiter, Raphael, Concin, Nicole, Moll, Ute, Zeilinger, Robert, Schmitt, Wolfgang, Sehouli, Jalid, Kulbe, Hagen, Ray-Coquard, Isabelle, Zeimet, Alain, Raspagliesi, Francesco, Zamagni, Claudio, Vergote, Ignace, Lorusso, Domenica, Bullinger, Lars, Braicu, Elena Ioana, and Damm, Frederik

Published
2023
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14. Clonal Hematopoiesis Is Common in Unrelated Stem Cell Donors but Has No Impact on Patient Outcome after Hematopoietic Stem Cell Transplantation

Author

Schetelig, Johannes, Damm, Frederik, Günther, Ulf - Peter, Baldauf, Henning, Rave, Carina, Koster, Linda, Schöfl, Gerhard, Klussmeier, Anja, Menghrajani, Kamal, Bolton, Kelly L., Rücker-Braun, Elke, Heidenreich, Falk, Münn, Marie, Fuhrmann, Markus, Visco, Ilaria, Frick, Mareike, Hablesreiter, Raphael, Arends, Christopher Maximilian, de Wreede, Liesbeth C., Nesterenko, Olena, Stelljes, Matthias, Bug, Gesine, Schröder, Thomas, Moiseev, Ivan Sergeevich, Schoemans, Helene, Koenecke, Christian, Teipel, Raphael, von Bonin, Malte, Bullinger, Lars, Bornhäuser, Martin, van den Brink, Marcel R.M., Schmidt, Alexander H., Lange, Vinzenz, Peric, Zinaida, and Penack, Olaf

Published
2023
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15. Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

Author

Frick, Mareike, primary, Chan, Willy, additional, Arends, Christopher Maximilian, additional, Hablesreiter, Raphael, additional, Halik, Adriane, additional, Heuser, Michael, additional, Michonneau, David, additional, Blau, Olga, additional, Hoyer, Kaja, additional, Christen, Friederike, additional, Galan-Sousa, Joel, additional, Noerenberg, Daniel, additional, Wais, Verena, additional, Stadler, Michael, additional, Yoshida, Kenichi, additional, Schetelig, Johannes, additional, Schuler, Esther, additional, Thol, Felicitas, additional, Clappier, Emmanuelle, additional, Christopeit, Maximilian, additional, Ayuk, Francis, additional, Bornhäuser, Martin, additional, Blau, Igor Wolfgang, additional, Ogawa, Seishi, additional, Zemojtel, Tomasz, additional, Gerbitz, Armin, additional, Wagner, Eva M., additional, Spriewald, Bernd M., additional, Schrezenmeier, Hubert, additional, Kuchenbauer, Florian, additional, Kobbe, Guido, additional, Wiesneth, Markus, additional, Koldehoff, Michael, additional, Socié, Gérard, additional, Kroeger, Nicolaus, additional, Bullinger, Lars, additional, Thiede, Christian, additional, and Damm, Frederik, additional

Published
2019
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17. Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes.

Author

Noerenberg D, Briest F, Hennch C, Yoshida K, Hablesreiter R, Takeuchi Y, Ueno H, Staiger AM, Ziepert M, Asmar F, Locher BN, Toth E, Weber T, Amini RM, Klapper W, Bouzani M, Poeschel V, Rosenwald A, Held G, Campo E, Ishaque N, Stamatopoulos K, Kanellis G, Anagnostopoulos I, Bullinger L, Goldschmidt N, Zinzani PL, Bödör C, Rosenquist R, Vassilakopoulos TP, Ott G, Ogawa S, and Damm F

Subjects
Humans, Female, Rituximab therapeutic use, Antibodies, Monoclonal, Murine-Derived therapeutic use, Prednisone therapeutic use, Vincristine therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Treatment Outcome, Guanine Nucleotide Exchange Factors therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse genetics
Abstract

Purpose: Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk stratification are lacking., Patients and Methods: To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions., Results: Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in TP53 -related genes ( TP63 , TP73 , and WWOX ) and identified novel SVs facilitating immune evasion ( DOCK8 and CD83 ). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg, ARID1A , P2RY8 , and PLXNC1 ) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact. CD58 mutations (31%) showed the strongest association with worse PFS (hazard ratio [HR], 2.52 [95% CI, 1.50 to 4.21]; P < .001) and overall survival (HR, 2.33 [95% CI, 1.14 to 4.76]; P = .02). IPI high-risk patients with mutated CD58 demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the CD58 mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast, DUSP2 -mutated patients (24%) displayed durable responses (PFS: HR, 0.2 [95% CI, 0.07 to 0.55]; P = .002) and prolonged OS (HR, 0.11 [95% CI, 0.01 to 0.78]; P = .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS and OS rates of 93% and 98%, respectively., Conclusion: This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification. DUSP2 and CD58 mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.

Published
2024
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