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1. Investigator choice of standard therapy versus sequential novel therapy arms in the treatment of relapsed follicular lymphoma (REFRACT): study protocol for a multi-centre, open-label, randomised, phase II platform trial

Author

McIlroy, Graham, Lax, Siân, Gaskell, Charlotte, Jackson, Aimee, Rhodes, Malcolm, Seale, Tania, Fox, Sonia, Hopkins, Lousie, Okosun, Jessica, Barrington, Sally F., Ringshausen, Ingo, Ramsay, Alan G., Calaminici, Maria, Linton, Kim, and Bishton, Mark

Published
2024
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3. Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

Author

Ecker, Veronika, Brandmeier, Lisa, Stumpf, Martina, Giansanti, Piero, Moreira, Aida Varela, Pfeuffer, Lisa, Fens, Marcel H.A.M., Lu, Junyan, Kuster, Bernhard, Engleitner, Thomas, Heidegger, Simon, Rad, Roland, Ringshausen, Ingo, Zenz, Thorsten, Wendtner, Clemens-Martin, Müschen, Markus, Jellusova, Julia, Ruland, Jürgen, and Buchner, Maike

Published
2023
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4. BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib

Author

Bonfiglio, Silvia, Sutton, Lesley-Ann, Ljungström, Viktor, Capasso, Antonella, Pandzic, Tatjana, Weström, Simone, Foroughi-Asl, Hassan, Skaftason, Aron, Gellerbring, Anna, Lyander, Anna, Gandini, Francesca, Gaidano, Gianluca, Trentin, Livio, Bonello, Lisa, Reda, Gianluigi, Bödör, Csaba, Stavroyianni, Niki, Tam, Constantine S., Marasca, Roberto, Forconi, Francesco, Panayiotidis, Panayiotis, Ringshausen, Ingo, Jaksic, Ozren, Frustaci, Anna Maria, Iyengar, Sunil, Coscia, Marta, Mulligan, Stephen P., Ysebaert, Loïc, Strugov, Vladimir, Pavlovsky, Carolina, Walewska, Renata, Österborg, Anders, Cortese, Diego, Ranghetti, Pamela, Baliakas, Panagiotis, Stamatopoulos, Kostas, Scarfò, Lydia, Rosenquist, Richard, and Ghia, Paolo

Published
2023
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5. MYC sensitises cells to apoptosis by driving energetic demand

Author

Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, von Kriegsheim, Alex, Patti, Gary J., Sims, Andrew H., Acosta, Juan Carlos, Brunton, Valerie, Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, and Finch, Andrew J.

Published
2022
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6. Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape

Author

Mangolini, Maurizio, Maiques-Diaz, Alba, Charalampopoulou, Stella, Gerhard-Hartmann, Elena, Bloehdorn, Johannes, Moore, Andrew, Giachetti, Giorgia, Lu, Junyan, Roamio Franklin, Valar Nila, Chilamakuri, Chandra Sekkar Reddy, Moutsopoulos, Ilias, Rosenwald, Andreas, Stilgenbauer, Stephan, Zenz, Thorsten, Mohorianu, Irina, D’Santos, Clive, Deaglio, Silvia, Hodson, Daniel J., Martin-Subero, Jose I., and Ringshausen, Ingo

Published
2022
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7. Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia

Author

Lu, Junyan, Cannizzaro, Ester, Meier-Abt, Fabienne, Scheinost, Sebastian, Bruch, Peter-Martin, Giles, Holly A. R., Lütge, Almut, Hüllein, Jennifer, Wagner, Lena, Giacopelli, Brian, Nadeu, Ferran, Delgado, Julio, Campo, Elías, Mangolini, Maurizio, Ringshausen, Ingo, Böttcher, Martin, Mougiakakos, Dimitrios, Jacobs, Andrea, Bodenmiller, Bernd, Dietrich, Sascha, Oakes, Christopher C., Zenz, Thorsten, and Huber, Wolfgang

Published
2021
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10. Der Einfluss von Therapie und zytogenetischen Veränderungen auf die Interaktion mit dem Tumormikroenvironment bei Patienten mit chronisch lymphatischer Leukämie

Author

Ringshausen, Ingo (Prof. Dr.), Ringshausen, Ingo (Prof. Dr.);Bassermann, Florian (Prof. Dr.), Braitsch, Krischan Oliver, Ringshausen, Ingo (Prof. Dr.), Ringshausen, Ingo (Prof. Dr.);Bassermann, Florian (Prof. Dr.), and Braitsch, Krischan Oliver

Abstract

Um die "environment mediated drug resistance" bei Patienten mit CLL im Verlauf der Erkrankung besser zu verstehen, wurden 65 sequentielle CLL Proben von 24 Patienten in einem Co-Kultur Modell untersucht. Durch ex-vivo Behandlung konnte die Chemosensitvität der primären CLL bestimmt werden. Die Genexpression von IL6 und NFKBIZ wurde in den Stromazellen nach CLL Kontakt untersucht, um Auswirkung klinischer Faktoren auf die Interaktion mit dem Tumormikromilleu besser zu verstehen., To better understand "environment mediated drug resistance" effects in patients with CLL, we analysed 65 sequential samples from 24 CLL patients in a co-culture model. Primary cells were treated with different cytotoxic drugs ex-vivo, to model the chemosensitivity of each patient. Further, IL6 and NFKBIZ mRNA levels were analysed in stromal cells after CLL contact, to better understand the impact of clinical features on the crosstalk between CLL cells and the microenvironment.

Published
2023

12. Robust CRISPR-Cas9 Genetic Editing of Primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells

Author

Mateos-Jaimez, Judith, Mangolini, Maurizio, Vidal, Anna, Kulis, Marta, Colomer, Dolors, Campo, Elias, Ringshausen, Ingo, Martin-Subero, Jose I, Maiques-Diaz, Alba, Ringshausen, Ingo [0000-0002-7247-311X], and Apollo - University of Cambridge Repository

Subjects
3201 Cardiovascular Medicine and Haematology, 32 Biomedical and Clinical Sciences, 3211 Oncology and Carcinogenesis
Published
2023

14. Drug-perturbation-based stratification of blood cancer

Author

Dietrich, Sascha, Oles, Matgorzata, Lu, Junyan, Sellner, Leopold, Anders, Simon, Velten, Britta, Wu, Bian, Hullein, Jennifer, Liberio, Michelle da Silva, Walther, Tatjana, Wagner, Lena, Rabe, Sophie, Ghidelli-Disse, Sonja, Bantscheff, Marcus, Oles, Andrzej K., Stabicki, Mikotaj, Mock, Andreas, Oakes, Christopher C., Wang, Shihui, Oppermann, Sina, Lukas, Marina, Kim, Vladislav, Sill, Martin, Benner, Axel, Jauch, Anna, Sutton, Lesley Ann, Young, Emma, Rosenquist, Richard, Liu, Xiyang, Jethwa, Alexander, Lee, Kwang Seok, Lewis, Joe, Putzker, Kerstin, Lutz, Christoph, Rossi, Davide, Mokhir, Andriy, Oellerich, Thomas, Zirlik, Katja, Herling, Marco, Nguyen-Khac, Florence, Plass, Christoph, Andersson, Emma, Mustjoki, Satu, von Kalle, Christof, Ho, Anthony D., Hensel, Manfred, Durig, Jan, Ringshausen, Ingo, Zapatka, Marc, Huber, Wolfgang, and Zenz, Thorsten

Subjects
Drugs -- Dosage and administration, Methylation -- Analysis, Cancer cells -- Research, Chronic lymphocytic leukemia -- Research, Gene expression -- Analysis, Health care industry
Abstract

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care., Introduction The clinical response to anticancer agents is heterogeneous, which is a major barrier to effective cancer care. Being able to more accurately predict response before choice of treatment would [...]

Published
2018
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15. Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

Author

Sub Biomol.Mass Spectrometry & Proteom., Chirurgie, Afd Pharmaceutics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Locomotion - Surgery (CA), Ecker, Veronika, Brandmeier, Lisa, Stumpf, Martina, Giansanti, Piero, Moreira, Aida Varela, Pfeuffer, Lisa, Fens, Marcel H.A.M., Lu, Junyan, Kuster, Bernhard, Engleitner, Thomas, Heidegger, Simon, Rad, Roland, Ringshausen, Ingo, Zenz, Thorsten, Wendtner, Clemens Martin, Müschen, Markus, Jellusova, Julia, Ruland, Jürgen, Buchner, Maike, Sub Biomol.Mass Spectrometry & Proteom., Chirurgie, Afd Pharmaceutics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Locomotion - Surgery (CA), Ecker, Veronika, Brandmeier, Lisa, Stumpf, Martina, Giansanti, Piero, Moreira, Aida Varela, Pfeuffer, Lisa, Fens, Marcel H.A.M., Lu, Junyan, Kuster, Bernhard, Engleitner, Thomas, Heidegger, Simon, Rad, Roland, Ringshausen, Ingo, Zenz, Thorsten, Wendtner, Clemens Martin, Müschen, Markus, Jellusova, Julia, Ruland, Jürgen, and Buchner, Maike

Published
2023

17. Negative feedback regulation of MAPK signaling is an important driver of CLL progression

Author

Ecker, Veronika, primary, Brandmeier, Lisa, additional, Stumpf, Martina, additional, Giansanti, Piero, additional, Moreira, Aida Varela, additional, Pfeuffer, Lisa, additional, Fens, Marcel, additional, Lu, Junyan, additional, Küster, Bernhard, additional, Engleitner, Thomas, additional, Heidegger, Simon, additional, Ringshausen, Ingo, additional, Zenz, Thorsten, additional, Wendtner, Clemens, additional, Müschen, Markus, additional, Ruland, Jürgen, additional, and Buchner, Maike, additional

Published
2023
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18. Transforming Growth Factor-Beta Orchestrates Tumour and Bystander Cells in B-Cell Non-Hodgkin Lymphoma

Author

Timmins, Matthew A, Ringshausen, Ingo, Timmins, Matthew A [0000-0002-7127-7395], Ringshausen, Ingo [0000-0002-7247-311X], and Apollo - University of Cambridge Repository

Subjects
TGFB, B-cell lymphoma, microenvironment
Abstract

Transforming growth factor-beta (TGFB) is a critical regulator of normal haematopoiesis. Dysregulation of the TGFB pathway is associated with numerous haematological malignancies including myelofibrosis, acute myeloid leukaemia, and lymphoid disorders. TGFB has classically been seen as a negative regulator of proliferation in haematopoiesis whilst stimulating differentiation and apoptosis, as required to maintain homeostasis. Tumours frequently develop intrinsic resistant mechanisms to homeostatic TGFB signalling to antagonise its tumour-suppressive functions. Furthermore, elevated levels of TGFB enhance pathogenesis through modulation of the immune system and tumour microenvironment. Here, we review recent advances in the understanding of TGFB signalling in B-cell malignancies with a focus on the tumour microenvironment. Malignant B-cells harbour subtype-specific alterations in TGFB signalling elements including downregulation of surface receptors, modulation of SMAD signalling proteins, as well as genetic and epigenetic aberrations. Microenvironmental TGFB generates a protumoural niche reprogramming stromal, natural killer (NK), and T-cells. Increasingly, evidence points to complex bi-directional cross-talk between cells of the microenvironment and malignant B-cells. A greater understanding of intercellular communication and the context-specific nature of TGFB signalling may provide further insight into disease pathogenesis and future therapeutic strategies.

Published
2022

20. Negative Feedback Regulation of MAPK Signaling Is an Important Driver of CLL Progression

Author

Brandmeier, Lisa, primary, Ecker, Veronika, additional, Stumpf, Martina, additional, Giansanti, Piero, additional, Varela Moreira, Aida, additional, Pfeuffer, Lisa, additional, Fens, Marcel, additional, Lu, Junyan, additional, Küster, Bernhard, additional, Engleitner, Thomas, additional, Heidegger, Simon, additional, Ringshausen, Ingo, additional, Zenz, Thorsten, additional, Wendtner, Clemens-Martin, additional, Müschen, Markus, additional, Ruland, Jürgen, additional, and Buchner, Maike, additional

Published
2022
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21. Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia

Author

Mangolini, Maurizio, Götte, Frederik, Moore, Andrew, Ammon, Tim, Oelsner, Madlen, Lutzny-Geier, Gloria, Klein-Hitpass, Ludger, Williamson, James C., Lehner, Paul J., Dürig, Jan, Möllmann, Michael, Rásó-Barnett, Lívia, Hughes, Katherine, Santoro, Antonella, Méndez-Ferrer, Simón, Oostendorp, Robert A. J., Zimber-Strobl, Ursula, Peschel, Christian, Hodson, Daniel J., Schmidt-Supprian, Marc, and Ringshausen, Ingo

Published
2018
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22. Protein Kinase C-β-Dependent Activation of NF-κB in Stromal Cells Is Indispensable for the Survival of Chronic Lymphocytic Leukemia B Cells In Vivo

Author

Lutzny, Gloria, Kocher, Thomas, Schmidt-Supprian, Marc, Rudelius, Martina, Klein-Hitpass, Ludger, Finch, Andrew J., Dürig, Jan, Wagner, Michaela, Haferlach, Claudia, Kohlmann, Alexander, Schnittger, Susanne, Seifert, Marc, Wanninger, Stefan, Zaborsky, Nadja, Oostendorp, Robert, Ruland, Jürgen, Leitges, Michael, Kuhnt, Toni, Schäfer, Yvonne, Lampl, Benedikt, Peschel, Christian, Egle, Alexander, and Ringshausen, Ingo

Published
2013
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23. MYC sensitises cells to apoptosis by driving energetic demand

Author

Wellcome Trust, Cancer Research UK, Barts Charity, Medical Research Council (UK), Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, Kriegsheim, Alexvon, Patti, Gary J., Sim, Andrew H., Acosta, Juan C., Brunton, Valerie G., Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, Finch, Andrew J., Wellcome Trust, Cancer Research UK, Barts Charity, Medical Research Council (UK), Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, Kriegsheim, Alexvon, Patti, Gary J., Sim, Andrew H., Acosta, Juan C., Brunton, Valerie G., Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, and Finch, Andrew J.

Abstract

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

Published
2022

31. NOTCH1 drives immune-escape mechanisms in B cell malignancies

Author

Mangolini, Maurizio, primary, Maiques-Diaz, Alba, additional, Charalampopoulou, Stella, additional, Gerhard-Hartmann, Elena, additional, Bloehdorn, Johannes, additional, Moore, Andrew, additional, Lu, Junyan, additional, Franklin, Valar Nila Roamio, additional, Chilamakuri, Chandra Sekkar Reddy, additional, Moutsoupoulos, Ilias, additional, Rosenwald, Andreas, additional, Stilgenbauer, Stephan, additional, Zenz, Thorsten, additional, Mohorianu, Irina, additional, D’Santos, Clive, additional, Deaglio, Silvia, additional, Martin-Subero, Jose I., additional, and Ringshausen, Ingo, additional

Published
2021
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32. Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia

Author

Ecker, Veronika, Stumpf, Martina, Brandmeier, Lisa, Neumayer, Tanja, Pfeuffer, Lisa, Engleitner, Thomas, Ringshausen, Ingo, Nelson, Nina, Jücker, Manfred, Wanninger, Stefan, Zenz, Thorsten, Wendtner, Clemens, Manske, Katrin, Steiger, Katja, Rad, Roland, Müschen, Markus, Ruland, Jürgen, and Buchner, Maike

Subjects
Article, Cancer therapy, Chronic lymphocytic leukaemia, ddc
Published
2020

34. ZAP-70 constitutively regulates gene expression and protein synthesis in chronic lymphocytic leukemia

Author

Chen, Jingyu, primary, Sathiaseelan, Vijitha, additional, Moore, Andrew, additional, Tan, Shengjiang, additional, Chilamakuri, Chandra Sekkar Reddy, additional, Roamio Franklin, Valar Nila, additional, Shahsavari, Arash, additional, Jakwerth, Constanze A., additional, Hake, Sandra B., additional, Warren, Alan J., additional, Mohorianu, Irina, additional, D’Santos, Clive, additional, and Ringshausen, Ingo, additional

Published
2021
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37. Abstract PO-62: Overcoming venetoclax resistance in B-cell malignancies by antagonism of stromal TGF-beta-mediated drug resistance

Author

Park, Eugene, primary, Chen, Jingyu, additional, Moore, Andrew, additional, Mangolini, Maurizio, additional, Byod, Joseph R., additional, Schjerven, Hilde, additional, Williamson, James C., additional, Lehner, Paul J., additional, Leitges, Michael, additional, Egle, Alexander, additional, Schmidt-Supprian, Marc, additional, Frietze, Seth, additional, and Ringshausen, Ingo, additional

Published
2020
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40. Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance

Author

Park, Eugene, primary, Chen, Jingyu, additional, Moore, Andrew, additional, Mangolini, Maurizio, additional, Santoro, Antonella, additional, Boyd, Joseph R., additional, Schjerven, Hilde, additional, Ecker, Veronika, additional, Buchner, Maike, additional, Williamson, James C., additional, Lehner, Paul J., additional, Gasparoli, Luca, additional, Williams, Owen, additional, Bloehdorn, Johannes, additional, Stilgenbauer, Stephan, additional, Leitges, Michael, additional, Egle, Alexander, additional, Schmidt-Supprian, Marc, additional, Frietze, Seth, additional, and Ringshausen, Ingo, additional

Published
2020
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44. The Functional Role of Zeta-Chain-Associated Protein 70 in the Pathogenesis of B-Cell Chronic Lymphocytic Leukemia

Author

Ringshausen, Ingo (Priv.-Doz. Dr.), Ringshausen, Ingo (Priv.-Doz. Dr.);Küster, Bernhard (Prof. Dr.), Jakwerth, Constanze Anneliese, Ringshausen, Ingo (Priv.-Doz. Dr.), Ringshausen, Ingo (Priv.-Doz. Dr.);Küster, Bernhard (Prof. Dr.), and Jakwerth, Constanze Anneliese

Abstract

The aim of this thesis was to investigate the functional role of the prognostic factor ZAP70 in chronic lymphocytic leukemia. The results show that ZAP70 can modify gene expression in leukemic B cells through a mechanism that is distinct from its role as a receptor associated kinase. ZAP70 can translocate to the nucleus in CLL cells, mediated via its kinase domain. The nuclear expression of ZAP70 does affect gene expression likely through an epigenetic mechanism. The altered gene expression in ZAP70-positive CLL cells effects the reduction of GSK3-beta expression, which subsequently stabilises the anti-apoptotic protein Mcl-1. Mcl-1 facilitates resistance to programmed cell death, contributing to the dismal prognosis of ZAP70-positive CLL., Das Ziel dieser Arbeit war es die funktionelle Rolle des Prognosefaktors ZAP70 in der CLL zu untersuchen. Die Ergebnisse zeigen, dass ZAP70 die Genexpression in leukämischen B-Zellen mithilfe eines Mechanismus modifizieren kann, der unabhängig von seiner Rolle als Rezeptor-assoziierte Kinase ist. ZAP70 kann mithilfe seiner Kinasedomäne in den Zellkern translozieren. Die nukleäre Expression von ZAP70 beeinflusst die Genexpression wahrscheinlich durch einen epigenetischen Mechanismus, was u.a. zur Reduktion der GSK3-beta-Expression führt. Die folgliche Stabilisierung des anti-apoptotischen Mcl-1 ermöglicht Resistenz gegen den programmierten Zelltod und trägt so zu der ungünstigen Prognose der ZAP70-positven CLL bei.

Published
2016

46. Interleukin-21 und CpG-Oligonukleotide: Untersuchungen zur Apoptoseinduktion bei B-Zell chronisch lymphatischer Leukämie

Author

Ringshausen, Ingo (Priv.-Doz. Dr.), Ringshausen, Ingo (Priv.-Doz. Dr.);Krackhardt, Angela (Prof. Dr.), Lackermeier, Angela, Ringshausen, Ingo (Priv.-Doz. Dr.), Ringshausen, Ingo (Priv.-Doz. Dr.);Krackhardt, Angela (Prof. Dr.), and Lackermeier, Angela

Abstract

Interleukin-21 (IL-21) und CpG rufen in B-CLL-Zellen (mit und ohne Stromasupport) in signifikantem Ausmaß caspaseabhängig Apoptose hervor. Diese wird über Tyrosin- und Serinphosphorylierung an STATs vermittelt, die zur Expressionsminderung von Bcl-2 und Bcl-xl führen. IL-21 alleine hat, über Stabilisierung von Bax und Bim, nur geringes pro-apoptotisches Potential. Abhängig von ihrem ZAP-70-Status können CLL-Zellen, über Regulation von Bim und Bax, pro-oder anti-apoptotisch auf CpG reagieren., Interleukin-21 (IL-21) and CpG oligonucleotides significantly induce caspase-dependent apoptosis in B-CLL cells, even when cultured with stromal cells. They cause phosphorylation on tyrosine and serine residues of STATs which lead to a decreased expression of bcl-2 and bcl-xl. IL-21 alone shows less proapoptotic potential by stabilization of bax and bim. By regulation of bim and bax, CpG can have pro- or antiapoptotic effects on CLL cells, depending on their ZAP-70 expression.

Published
2015

47. Guideline for the treatment of chronic lymphocytic leukaemia

Author

Schuh, Anna H., primary, Parry-Jones, Nilima, additional, Appleby, Niamh, additional, Bloor, Adrian, additional, Dearden, Claire E., additional, Fegan, Christopher, additional, Follows, George, additional, Fox, Christopher P., additional, Iyengar, Sunil, additional, Kennedy, Ben, additional, McCarthy, Helen, additional, Parry, Helen M., additional, Patten, Piers, additional, Pettitt, Andrew R., additional, Ringshausen, Ingo, additional, Walewska, Renata, additional, and Hillmen, Peter, additional

Published
2018
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48. Drug-perturbation-based stratification of blood cancer

Author

Dietrich, Sascha, primary, Oleś, Małgorzata, additional, Lu, Junyan, additional, Sellner, Leopold, additional, Anders, Simon, additional, Velten, Britta, additional, Wu, Bian, additional, Hüllein, Jennifer, additional, da Silva Liberio, Michelle, additional, Walther, Tatjana, additional, Wagner, Lena, additional, Rabe, Sophie, additional, Ghidelli-Disse, Sonja, additional, Bantscheff, Marcus, additional, Oleś, Andrzej K., additional, Słabicki, Mikołaj, additional, Mock, Andreas, additional, Oakes, Christopher C., additional, Wang, Shihui, additional, Oppermann, Sina, additional, Lukas, Marina, additional, Kim, Vladislav, additional, Sill, Martin, additional, Benner, Axel, additional, Jauch, Anna, additional, Sutton, Lesley Ann, additional, Young, Emma, additional, Rosenquist, Richard, additional, Liu, Xiyang, additional, Jethwa, Alexander, additional, Lee, Kwang Seok, additional, Lewis, Joe, additional, Putzker, Kerstin, additional, Lutz, Christoph, additional, Rossi, Davide, additional, Mokhir, Andriy, additional, Oellerich, Thomas, additional, Zirlik, Katja, additional, Herling, Marco, additional, Nguyen-Khac, Florence, additional, Plass, Christoph, additional, Andersson, Emma, additional, Mustjoki, Satu, additional, von Kalle, Christof, additional, Ho, Anthony D., additional, Hensel, Manfred, additional, Dürig, Jan, additional, Ringshausen, Ingo, additional, Zapatka, Marc, additional, Huber, Wolfgang, additional, and Zenz, Thorsten, additional

Published
2017
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49. Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome

Author

Till, Kathleen J., primary, Allen, John C., additional, Talab, Fatima, additional, Lin, Ke, additional, Allsup, David, additional, Cawkwell, Lynn, additional, Bentley, Alison, additional, Ringshausen, Ingo, additional, Duckworth, Andrew D., additional, Pettitt, Andrew R., additional, Kalakonda, Nagesh, additional, and Slupsky, Joseph R., additional

Published
2017
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50. Verstärkung der Zytotoxizität der anti-CD22 Immuntoxine durch Bryostatin 1 in B-Zelllymphomen

Author

Ringshausen, Ingo (Priv.-Doz. Dr.), Ringshausen, Ingo (Priv.-Doz. Dr.);Schmid, Roland M. (Prof. Dr.);Busch, Dirk (Prof. Dr.), Biberacher, Viola Maria, Ringshausen, Ingo (Priv.-Doz. Dr.), Ringshausen, Ingo (Priv.-Doz. Dr.);Schmid, Roland M. (Prof. Dr.);Busch, Dirk (Prof. Dr.), and Biberacher, Viola Maria

Abstract

Die chronisch lymphatische Leukämie (CLL) bleibt trotz intensiver klinischer und präklinischer Forschung bislang eine unheilbare Erkrankung. In dieser Arbeit wurde ein präklinisches Modell zur Optimierung der Therapie mit monoklonalen CD22-Immuntoxinen durch Bryostatin entwickelt. An primären CLL-Zellen konnte in vitro gezeigt werden, dass Bryostatin die Immuntoxinbindung durch Erhöhung der CD22-Expression verbessert und durch Veränderung des Proteinkinase-C-Expressionsprofils die CLL-Zellen zusätzlich für das Immuntoxin sensibilisiert. Kurzzeitig auftretende antiapoptotische Wirkungen von Bryostatin können durch sequentielle Gabe beider Medikamente umgangen werden. Die Ergebnisse ließen sich zudem an verschiedenen Lymphomzelllinien reproduzieren. Das Modell stellt somit einen vielversprechenden Ansatz für klinische Studien an Patienten mit verschiedenen B-Zelllymphomen dar., In spite of intensive effort in clinical and preclinical research chronic lymphocytic leukemia still remains an incurable disease. In this work we developed a preclinical model to improve therapy with monoclonal CD22-immunotoxins through bryostatin. In primary CLL-cells it could be demonstrated in vitro that bryostatin improves binding of the immunotoxin by increasing CD22 expression and additionally sensitizes CLL cells for immunotoxin through alteration of PKC expression. Short-time antiapoptotic effects of bryostatin can be circumvented by sequential application of both drugs. These results could be reproduced in various lymphoma cell lines. This model thus represents a promising approach for clinical studies in patients with various types of B cell lymphoma.

Published
2014

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