Search

Your search keyword '"Koschmieder A"' showing total 2,846 results
Start Over Author "Koschmieder A"
2,846 results on '"Koschmieder A"'

3. ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options

Author

Kiladjian, Jean-Jacques, Marin, Francisca Ferrer, Al-Ali, Haifa Kathrin, Alvarez-Larrán, Alberto, Beggiato, Eloise, Bieniaszewska, Maria, Breccia, Massimo, Buxhofer-Ausch, Veronika, Cerna, Olga, Crisan, Ana-Manuela, Danaila, Catalin Doru, De Stefano, Valerio, Döhner, Konstanze, Empson, Victoria, Gora-Tybor, Joanna, Griesshammer, Martin, Grosicki, Sebastian, Guglielmelli, Paola, García-Gutierrez, Valentin, Heidel, Florian H., Illés, Arpád, Tomuleasa, Ciprian, James, Chloe, Koschmieder, Steffen, Krauth, Maria-Theresa, Krejcy, Kurt, Lazaroiu, Mihaela-Cornelia, Mayer, Jiri, Nagy, Zsolt György, Nicolini, Franck-Emmanuel, Palandri, Francesca, Pappa, Vassiliki, Reiter, Andreas Johannes, Sacha, Tomasz, Schlager, Stefanie, Schmidt, Stefan, Terpos, Evangelos, Unger, Martin, Wölfler, Albert, Cirici, Blanca Xicoy, and Klade, Christoph

Published
2024
Full Text
View/download PDF

8. Real-world analysis of ruxolitinib in myelofibrosis: interim results focusing on patients who were naïve to JAK inhibitor therapy treated within the JAKoMo non-interventional, phase IV trial

Author

Koschmieder, Steffen, Isfort, Susanne, Schulte, Clemens, Jacobasch, Lutz, Geer, Thomas, Reiser, Marcel, Koenigsmann, Michael, Heinrich, Bernhard, Wehmeyer, Jürgen, von der Heyde, Eyck, Tesch, Hans, Gröschl, Benedikt, Bachhuber, Petra, Großer, Susanne, and Pahl, Heike L.

Published
2023
Full Text
View/download PDF

9. Activating mutations in JAK2 and CALR differentially affect intracellular calcium flux in store operated calcium entry

Author

Vikas Bhuria, Tobias Franz, Conny Baldauf, Martin Böttcher, Nicolas Chatain, Steffen Koschmieder, Tim H. Brümmendorf, Dimitrios Mougiakakos, Burkhart Schraven, Sascha Kahlfuß, and Thomas Fischer

Subjects
Calcium flux, EPO signaling, TPO signaling, MPNs, JAK2-V617F, CALR mutation, Medicine, Cytology, QH573-671
Abstract

Abstract Background Calcium (Ca2+) signaling regulates various vital cellular functions, including integrin activation and cell migration. Store-operated calcium entry (SOCE) via calcium release-activated calcium (CRAC) channels represents a major pathway for Ca2+ influx from the extracellular space in multiple cell types. The impact of JAK2-V617F and CALR mutations which are disease initiating in myeloproliferative neoplasms (MPN) on SOCE, calcium flux from the endoplasmic reticulum (ER) to the cytosol, and related key signaling pathways in the presence or absence of erythropoietin (EPO) or thrombopoietin (TPO) is poorly understood. Thus, this study aimed to elucidate the effects of these mutations on the aforementioned calcium dynamics, in cellular models of MPN. Methods Intracellular Ca2+ levels were measured over a time frame of 0–1080 s in Fura-2 AM labeled myeloid progenitor 32D cells expressing various mutations (JAK2-WT/EpoR, JAK2-V617F/EpoR; CALR-WT/MPL, CALR-ins5/MPL, and del52/MPL). Basal Ca2+ concentrations were assessed from 0–108 s. Subsequently, cells were stimulated with EPO/TPO in Ca2+-free Ringer solution, measuring Ca2+ levels from 109–594 s (store depletion). Then, 2 mM of Ca2+ buffer resembling physiological concentrations was added to induce SOCE, and Ca2+ levels were measured from 595–1080 s. Fura-2 AM emission ratios (F340/380) were used to quantify the integrated Ca2+ signal. Statistical significance was assessed by unpaired Student's t-test or Mann–Whitney-U-test, one-way or two-way ANOVA followed by Tukey's multiple comparison test. Results Following EPO stimulation, the area under the curve (AUC) representing SOCE significantly increased in 32D-JAK2-V617F cells compared to JAK2-WT cells. In TPO-stimulated CALR cells, we observed elevated Ca2+ levels during store depletion and SOCE in CALR-WT cells compared to CALR-ins5 and del52 cells. Notably, upon stimulation, key components of the Ca2+ signaling pathways, including PLCγ-1 and IP3R, were differentially affected in these cell lines. Hyper-activated PLCγ-1 and IP3R were observed in JAK2-V617F but not in CALR mutated cells. Inhibition of calcium regulatory mechanisms suppressed cellular growth and induced apoptosis in JAK2-V617F cells. Conclusions This report highlights the impact of JAK2 and CALR mutations on Ca2+ flux (store depletion and SOCE) in response to stimulation with EPO and TPO. The study shows that the JAK2-V617F mutation strongly alters the regulatory mechanism of EpoR/JAK2-dependent intracellular calcium balance, affecting baseline calcium levels, EPO-induced calcium entry, and PLCγ-1 signaling pathways. Our results reveal an important role of calcium flux in the homeostasis of JAK2-V617F positive cells.

Published
2024
Full Text
View/download PDF

10. Cloud-Based ICME Software Training

Author

Koschmieder, Lukas, Altenfeld, Ralph, Eiken, Janin, Böttger, Bernd, and Schmitz, Georg J.

Abstract

Hands-on type training of Integrated Computational Materials Engineering (ICME) is characterized by assisted application and combination of multiple simulation software tools and data. In this paper, we present recent experiences in establishing a cloud-based infrastructure to enable remote use of dedicated commercial and open access simulation tools during an interactive online training event. In the first part, we summarize the hardware and software requirements and illustrate how these have been met using cloud hardware services, a simulation platform environment, a suitable communication channel, common workspaces, and more. The second part of the article focuses (i) on the requirements for suitable online hands-on training material and (ii) on details of some of the approaches taken. Eventually, the practical experiences gained during three consecutive online training courses held in September 2020 with 35 nominal participants each, are discussed in detail.

Published
2021

11. Calreticulin and JAK2V617F driver mutations induce distinct mitotic defects in myeloproliferative neoplasms

Author

Kristin Holl, Nicolas Chatain, Susanne Krapp, Julian Baumeister, Tiago Maié, Sarah Schmitz, Anja Scheufen, Nathalie Brock, Steffen Koschmieder, and Daniel Moreno-Andrés

Subjects
Medicine, Science
Abstract

Abstract Myeloproliferative neoplasms (MPNs) encompass a diverse group of hematologic disorders driven by mutations in JAK2, CALR, or MPL. The prevailing working model explaining how these driver mutations induce different disease phenotypes is based on the decisive influence of the cellular microenvironment and the acquisition of additional mutations. Here, we report increased levels of chromatin segregation errors in hematopoietic cells stably expressing CALRdel52 or JAK2V617F mutations. Our investigations employing murine 32DMPL and human erythroleukemic TF-1MPL cells demonstrate a link between CALRdel52 or JAK2V617F expression and a compromised spindle assembly checkpoint (SAC), a phenomenon contributing to error-prone mitosis. This defective SAC is associated with imbalances in the recruitment of SAC factors to mitotic kinetochores upon CALRdel52 or JAK2V617F expression. We show that JAK2 mutant CD34 + MPN patient-derived cells exhibit reduced expression of the master mitotic regulators PLK1, aurora kinase B, and PP2A catalytic subunit. Furthermore, the expression profile of mitotic regulators in CD34 + patient-derived cells allows to faithfully distinguish patients from healthy controls, as well as to differentiate primary and secondary myelofibrosis from essential thrombocythemia and polycythemia vera. Altogether, our data suggest alterations in mitotic regulation as a potential driver in the pathogenesis in MPN.

Published
2024
Full Text
View/download PDF

17. Step-in dosing of bosutinib in pts with chronic phase chronic myeloid leukemia (CML) after second-generation tyrosine kinase inhibitor (TKI) therapy: results of the Bosutinib Dose Optimization (BODO) Study

Author

Isfort, Susanne, Manz, Kirsi, Teichmann, Lino L., Crysandt, Martina, Burchert, Andreas, Hochhaus, Andreas, Saussele, Susanne, Kiani, Alexander, Göthert, Joachim R., Illmer, Thomas, Schafhausen, Philippe, Al-Ali, Haifa Kathrin, Stegelmann, Frank, Hänel, Mathias, Pfeiffer, Tim, Giagounidis, Aristoteles, Franke, Georg-Nikolaus, Koschmieder, Steffen, Fabarius, Alice, Ernst, Thomas, Warnken-Uhlich, Mareille, Wolber, Uta, Kohn, Denise, Pfirrmann, Markus, Wolf, Dominik, and Brümmendorf, Tim H.

Published
2023
Full Text
View/download PDF

19. Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model

Author

Langhammer, Melanie, Schöpf, Julia, Jaquet, Timo, Horn, Katharina, Angel, Moritz, Spohr, Corinna, Christen, Daniel, Uhl, Franziska Maria, Maié, Tiago, Jacobi, Henrike, Feyerabend, Thorsten B., Huber, Julia, Panning, Marcus, Sitaru, Cassian, Costa, Ivan, Zeiser, Robert, Aumann, Konrad, Becker, Heiko, Braunschweig, Till, Koschmieder, Steffen, Shoumariyeh, Khalid, Huber, Michael, Schemionek-Reinders, Mirle, Brummer, Tilman, and Halbach, Sebastian

Published
2023
Full Text
View/download PDF

20. Adversarial cycle-consistent synthesis of cerebral microbleeds for data augmentation

Author

Faryna, Khrystyna, Koschmieder, Kevin, Paul, Marcella M., Heuvel, Thomas van den, van der Eerden, Anke, Manniesing, Rashindra, and van Ginneken, Bram

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

We propose a novel framework for controllable pathological image synthesis for data augmentation. Inspired by CycleGAN, we perform cycle-consistent image-to-image translation between two domains: healthy and pathological. Guided by a semantic mask, an adversarially trained generator synthesizes pathology on a healthy image in the specified location. We demonstrate our approach on an institutional dataset of cerebral microbleeds in traumatic brain injury patients. We utilize synthetic images generated with our method for data augmentation in cerebral microbleeds detection. Enriching the training dataset with synthetic images exhibits the potential to increase detection performance for cerebral microbleeds in traumatic brain injury patients., Comment: Accepted in Medical Imaging meets NIPS Workshop, NIPS 2020

Published
2021

21. Proinflammatory phenotype of iPS cell-derived JAK2 V617F megakaryocytes induces fibrosis in 3D in vitro bone marrow niche

Author

Flosdorf, Niclas, Böhnke, Janik, de Toledo, Marcelo A.S., Lutterbach, Niklas, Lerma, Vanesa Gómez, Graßhoff, Martin, Olschok, Kathrin, Gupta, Siddharth, Tharmapalan, Vithurithra, Schmitz, Susanne, Götz, Katrin, Schüler, Herdit M., Maurer, Angela, Sontag, Stephanie, Küstermann, Caroline, Seré, Kristin, Wagner, Wolfgang, Costa, Ivan G., Brümmendorf, Tim H., Koschmieder, Steffen, Chatain, Nicolas, Castilho, Miguel, Schneider, Rebekka K., and Zenke, Martin

Published
2024
Full Text
View/download PDF

23. Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

Author

Pritchard, Jessica E., Pearce, Juliette E., Snoeren, Inge A.M., Fuchs, Stijn N.R., Götz, Katrin, Peisker, Fabian, Wagner, Silke, Benabid, Adam, Lutterbach, Niklas, Klöker, Vanessa, Nagai, James S., Hannani, Monica T., Galyga, Anna K., Sistemich, Ellen, Banjanin, Bella, Flosdorf, Niclas, Bindels, Eric, Olschok, Kathrin, Biaesch, Katharina, Chatain, Nicolas, Bhagwat, Neha, Dunbar, Andrew, Sarkis, Rita, Naveiras, Olaia, Berres, Marie-Luise, Koschmieder, Steffen, Levine, Ross L., Costa, Ivan G., Gleitz, Hélène F.E., Kramann, Rafael, and Schneider, Rebekka K.

Published
2024
Full Text
View/download PDF

24. Longitudinal Assessment of Transfusion Intensity in Patients With JAK Inhibitor–Naive or –Experienced Myelofibrosis Treated With Momelotinib

Author

Harrison, Claire N., Mesa, Ruben, Talpaz, Moshe, Gupta, Vikas, Gerds, Aaron T., Perkins, Andrew, Goh, Yeow Tee, Fox, Maria Laura, McLornan, Donal, Palmer, Jeanne, Foltz, Lynda, Vannucchi, Alessandro, Koschmieder, Steffen, Passamonti, Francesco, Lee, Sung-Eun, Ellis, Catherine, Strouse, Bryan, Gonzalez Carreras, Francisco J., and Oh, Stephen T.

Published
2024
Full Text
View/download PDF

25. Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EBMT/ELN International Working Group

Author

Kröger, Nicolaus, Bacigalupo, Andrea, Barbui, Tiziano, Ditschkowski, Markus, Gagelmann, Nico, Griesshammer, Martin, Gupta, Vikas, Hamad, Nada, Harrison, Claire, Hernandez-Boluda, Juan Carlos, Koschmieder, Steffen, Jain, Tania, Mascarenhas, John, Mesa, Ruben, Popat, Uday R, Passamonti, Francesco, Polverelli, Nicola, Rambaldi, Alessandro, Robin, Marie, Salit, Rachel B, Schroeder, Thomas, Scott, Bart L, Tamari, Roni, Tefferi, Ayalew, Vannucchi, Alessandro M, McLornan, Donal P, and Barosi, Giovanni

Published
2024
Full Text
View/download PDF

26. Clinicohematologic and molecular response of essential thrombocythemia patients treated with pegylated interferon-α: a multi-center study of the German Study Group-Myeloproliferative Neoplasms (GSG-MPN)

Author

Stegelmann, Frank, Teichmann, Lino L., Heidel, Florian H., Crodel, Carl C., Ernst, Thomas, Kreil, Sebastian, Reiter, Andreas, Otten, Sara, Schauer, Stefanie, Körber, Ruth-Miriam, Kricheldorf, Kim, Isfort, Susanne, Döhner, Hartmut, Brümmendorf, Tim H., Griesshammer, Martin, Döhner, Konstanze, and Koschmieder, Steffen

Published
2023
Full Text
View/download PDF

28. Quantification of hematopoietic stem and progenitor cells by targeted DNA methylation analysis

Author

Ledio Bocova, Wouter Hubens, Cordula Engel, Steffen Koschmieder, Edgar Jost, and Wolfgang Wagner

Subjects
DNA methylation, Biomarker, Epigenetic, Hematopoietic stem cells, HSC, CD34, Medicine, Genetics, QH426-470
Abstract

Abstract Hematopoietic stem and progenitor cells (HSPCs) are quantified in daily clinical practice by flow cytometry. In this study, we provide proof of concept that HSPCs can also be estimated by targeted DNA methylation (DNAm) analysis. The DNAm levels at three individual CG dinucleotides (CpG sites) in the genes MYO1D, STK17A, and SP140 correlated with CD34+ cell numbers in mobilized peripheral blood and with blast counts in leukemia. In the future, such epigenetic biomarkers can support the evaluation of stem cell mobilization, HSPC harvesting, or blast count in leukemia.

Published
2023
Full Text
View/download PDF

29. Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

Author

Jessica E. Pritchard, Juliette E. Pearce, Inge A.M. Snoeren, Stijn N.R. Fuchs, Katrin Götz, Fabian Peisker, Silke Wagner, Adam Benabid, Niklas Lutterbach, Vanessa Klöker, James S. Nagai, Monica T. Hannani, Anna K. Galyga, Ellen Sistemich, Bella Banjanin, Niclas Flosdorf, Eric Bindels, Kathrin Olschok, Katharina Biaesch, Nicolas Chatain, Neha Bhagwat, Andrew Dunbar, Rita Sarkis, Olaia Naveiras, Marie-Luise Berres, Steffen Koschmieder, Ross L. Levine, Ivan G. Costa, Hélène F.E. Gleitz, Rafael Kramann, and Rebekka K. Schneider

Subjects
CP: Stem cell research, Biology (General), QH301-705.5
Abstract

Summary: The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.

Published
2024
Full Text
View/download PDF

38. Efficacy and safety of ruxolitinib in patients with newly-diagnosed polycythemia vera: futility analysis of the RuxoBEAT clinical trial of the GSG-MPN study group

Author

Koschmieder, Steffen, Isfort, Susanne, Wolf, Dominik, Heidel, Florian H., Hochhaus, Andreas, Schafhausen, Philippe, Griesshammer, Martin, Wolleschak, Denise, Platzbecker, Uwe, Döhner, Konstanze, Jost, Philipp J., Parmentier, Stefani, Schaich, Markus, von Bubnoff, Nikolas, Stegelmann, Frank, Maurer, Angela, Crysandt, Martina, Gezer, Deniz, Kortmann, Maike, Franklin, Jeremy, Frank, Julia, Hellmich, Martin, and Brümmendorf, Tim H.

Published
2023
Full Text
View/download PDF

41. The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling

Author

Kathrin Olschok, Bianca Altenburg, Marcelo A. S. de Toledo, Angela Maurer, Anne Abels, Fabian Beier, Deniz Gezer, Susanne Isfort, Katrin Paeschke, Tim H. Brümmendorf, Martin Zenke, Nicolas Chatain, and Steffen Koschmieder

Subjects
Myeloproliferative neoplasms (MPN), imetelstat (GRN163L), myelofibrosis (MF), induced pluripotent stem cells, telomere length (TL), JAK2V617F, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Imetelstat shows activity in patients with myeloproliferative neoplasms, including primary myelofibrosis (PMF) and essential thrombocythemia. Here, we describe a case of prolonged disease stabilization by imetelstat treatment of a high-risk PMF patient enrolled into the clinical study MYF2001. We confirmed continuous shortening of telomere length (TL) by imetelstat treatment but observed emergence and expansion of a KRAST58I mutated clone during the patient’s clinical course. In order to investigate the molecular mechanisms involved in the imetelstat treatment response, we generated induced pluripotent stem cells (iPSC) from this patient. TL of iPSC-derived hematopoietic stem and progenitor cells, which was increased after reprogramming, was reduced upon imetelstat treatment for 14 days. However, while imetelstat reduced clonogenic growth of the patient’s primary CD34+ cells, clonogenic growth of iPSC-derived CD34+ cells was not affected, suggesting that TL was not critically short in these cells. Also, the propensity of iPSC differentiation toward megakaryocytes and granulocytes was not altered. Using human TF-1MPL and murine 32DMPL cell lines stably expressing JAK2V617F or CALRdel52, imetelstat-induced reduction of viability was significantly more pronounced in CALRdel52 than in JAK2V617F cells. This was associated with an immediate downregulation of JAK2 phosphorylation and downstream signaling as well as a reduction of hTERT and STAT3 mRNA expression. Hence, our data demonstrate that imetelstat reduces TL and targets JAK/STAT signaling, particularly in CALR-mutated cells. Although the exact patient subpopulation who will benefit most from imetelstat needs to be defined, our data propose that CALR-mutated clones are highly vulnerable.

Published
2023
Full Text
View/download PDF

44. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study

Author

Abulafia, Adi Shacham, Al-Ali, Haifa Kathrin, Andreasson, Bjorn, Angona, Anna, Ayala, Rosa, Bang, Soo-Mee, Bank, Bruce, Barraco, Fiorenza, Beggiato, Eloise, Benghiat, Fleur Samantha, Bonifacio, MassimiliaNo, Bories, Claire, Borsaru, Gabriela, Brabrand, Mette, Braester, Andrei, Broliden, Andes, Buxhofer-Ausch, Veronika, Cambier, Nathalie, Caramella, Marianna, Carpentier, Benjamin, Cascavilla, Nicola, Castellano, Maria Giraldo, Chang, Hung, Chen, Chih-Cheng, Cheong, June-Won, Choi, Yunsuk, Choi, Philip, Corsetti, Maria Teresa, Cuadrado, Isabel Montero, Cunningham, Julia, Damaj, Gandhi Laurent, De Stefano, Valerio, Delage, Robert, Delgado, Regina Garcĺa, Diaz, Jose Miguel Torregrosa, Dombi, Péter, Dubruille, Viviane, Egyed, Miklós, El Fassi, Daniel, Elinder-Camburn, Anna, Elli, Elena Maria, Ellis, Martin, Fava, Carmen, Fazal, Salman, Fleischman, Angela, Foltz, Lynda, Fox, Laura, Gabrail, Nashat, Garcĺa-Gutiérrez, Jose Valentĺn, Gerds, Aaron, Girault, Stephane, Gisslinger, Heinz, Gluvacov, Alexandru, Goh, Yeow Tee, Göthert, Joachim, Granacher, Nikki, Grosicki, Sebastian, Gupta, Vikas, Hadjiev (Hadzhiev), Evgeni (Evgueniy), Hafraoui, Kaoutar, Hamed, Aryan, Harrison, Claire, Hasselbalch, Hans, Hauser, Hanns, Heaney, Mark, Hebart, Holger, Hernandez Rivas, Jesus Maria, Higuero Saavedra, Victor, Hillis, Christopher, Hou, Hsin-An, How, Jonathan, Huang, Daniel, Hus, Marek, Illés, Arpad, Isidori, Alessandro, Iurlo, Alessandra, Ivanov, Vadim, Johansson, Peter, Jung, Chul Won, Kiladjian, Jean-Jacques, Kirgner, Ilya, Koren-Michowitz, Maya, Koschmieder, Steffen, Kosztolanyi, Szabolcs Ors, Kreiniz, Natalia, Kuykendall, Andrew, Lambert, Jonathan, Laribi, Kamel, Lascaux, Axelle, Lavie, Noa, Lavie, David, Lazaroiu, Mihaela, Leahy, Michael, Lech-Maranda, Ewa, Lee, Sung-Eun, Lee, Won Sik, Legrand, Ollivier, Lemoli, Roberto, Liang, James, Lim, Sung-Nam, Loschi, Michael, Lucchesi, Alessandro, Macarie, Ioan, Marolleau, Jean-Pierre, Martelli, Maurizio, Mayer, Jiri, McCloskey, James, McDermott, Christopher, McLornan, Donal, McMahon, Brandon, Mehta, Priyanka, Mesa, Ruben, Mikala, Gábor, Milojkovic, Dragana, Mineur, Philippe, Mishchenko, Elena, Moon, Joon Ho, Nagy, Zsolt, Narayanan, Srinivasan, O'Connell, Casey, Ocroteala, Luminita, Oh, Stephen, Ojeda-Uribe, Mario, Ong, Kiat Hoe, Otegbeye, Folashade, Palmer, Jeanne, Pane, Fabrizio, Passamonti, Francesco, Patriarca, Andrea, Perkins, Andrew, Pietrantuono, Giuseppe, Plander, Mark, Platzbecker, Uwe, Prasad, Ritam, Prejzner, Witold, Rachow, Tobias, Radinoff, Atanas, Rejtő, László, Rinaldi, Ciro, Robak, Tadeusz, Rodriguez, Maria Angeles Fernandez, Ronson, Aaron, Ross, David, Sacha, Tomasz, Sadjadian, Parvis, Salar, Antonio, Santillana, Guillermo Sanz, Scheid, Christof, Schmidt, Aline, Severinsen, Marianne Tang, Stoeva, Vera, Szwedyk, Paweł, Tiribelli, Mario, Trautmann-Grill, Karolin, Trottier, Amy, Tzvetkov, Nikolay, van Droogenbroeck, Janusz, Vannucchi, Alessandro, Verstovsek, Srdan, Vianelli, Nicola, von Bubnoff, Nikolas, Wolf, Dominik, Woszczyk, Dariusz, Woźny, Tomasz, Wróbel, Tomasz, Xicoy, Blanca, Yeh, Su-Peng, Yoon, Sung-Soo, Gerds, Aaron T, Vannucchi, Alessandro M, Kuykendall, Andrew T, Lazaroiu, Mihaela C, Egyed, Miklos, Fox, Maria Laura, Harrison, Claire N, Klencke, Barbara J, Ro, Sunhee, Donahue, Rafe, and Kawashima, Jun

Published
2023
Full Text
View/download PDF

45. Breakthrough infections in MPN-COVID vaccinated patients

Author

Tiziano Barbui, Alessandra Carobbio, Arianna Ghirardi, Alessandra Iurlo, Valerio De Stefano, Marta Anna Sobas, Elisa Rumi, Elena Maria Elli, Francesca Lunghi, Mercedes Gasior Kabat, Beatriz Cuevas, Paola Guglielmelli, Massimiliano Bonifacio, Monia Marchetti, Alberto Alvarez-Larran, Laura Fox, Marta Bellini, Rosa Daffini, Giulia Benevolo, Gonzalo Carreno-Tarragona, Andrea Patriarca, Haifa Kathrin Al-Ali, Maria Marcio Miguel Andrade-Campos, Francesca Palandri, Claire Harrison, Maria Angeles Foncillas, Santiago Osorio, Steffen Koschmieder, Elena Magro Mazo, Jean-Jacques Kiladjian, Estefanía Bolaños Calderón, Florian H. Heidel, Keina Quiroz Cervantes, Martin Griesshammer, Valentin Garcia-Gutierrez, Alberto Marin Sanchez, Juan Carlos Hernandez-Boluda, Emma Lopez Abadia, Giuseppe Carli, Miguel Sagues Serrano, Rajko Kusec, Blanca Xicoy Cirici, Margarita Guenova, Begona Navas Elorza, Anna Angona, Edyta Cichocka, Anna Kulikowska de Nałęcz, Daniele Cattaneo, Cristina Bucelli, Silvia Betti, Oscar Borsani, Fabrizio Cavalca, Sara Carbonell, Natalia Curto-Garcia, Lina Benajiba, Alessandro Rambaldi, and Alessandro Maria Vannucchi

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2022
Full Text
View/download PDF

50. Exploiting Synthetic Lethality between Germline BRCA1 Haploinsufficiency and PARP Inhibition in JAK2V617F-Positive Myeloproliferative Neoplasms

Author

Max Bermes, Maria Jimena Rodriguez, Marcelo Augusto Szymanski de Toledo, Sabrina Ernst, Gerhard Müller-Newen, Tim Henrik Brümmendorf, Nicolas Chatain, Steffen Koschmieder, and Julian Baumeister

Subjects
myeloproliferative neoplasms, MPN, BRCA1, haploinsufficiency, olaparib, interferon-alpha, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., BRCA1). We investigated the therapeutic potential of targeting BRCA1 haploinsufficiency alongside the JAK2V617F driver mutation. We assessed the efficacy of combining the PARP inhibitor olaparib with interferon-alpha (IFNα) in CRISPR/Cas9-engineered Brca1+/− Jak2V617F-positive 32D cells. Olaparib treatment induced a higher number of DNA double-strand breaks, as demonstrated by γH2AX analysis through Western blot (p = 0.024), flow cytometry (p = 0.013), and confocal microscopy (p = 0.071). RAD51 foci formation was impaired in Brca1+/− cells compared to Brca1+/+ cells, indicating impaired homologous recombination repair due to Brca1 haploinsufficiency. Importantly, olaparib enhanced apoptosis while diminishing cell proliferation and viability in Brca1+/− cells compared to Brca1+/+ cells. These effects were further potentiated by IFNα. Olaparib induced interferon-stimulated genes and increased endogenous production of IFNα in Brca1+/− cells. These responses were abrogated by STING inhibition. In conclusion, our findings suggest that the combination of olaparib and IFNα presents a promising therapeutic strategy for MPN patients by exploiting the synthetic lethality between germline BRCA1 mutations and the JAK2V617F MPN driver mutation.

Published
2023
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results