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119 results on '"Jenni, Silvia"'

1. CD19-CD28: an affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy

Author

Sam, Johannes, Hofer, Thomas, Kuettel, Christine, Claus, Christina, Thom, Jenny, Herter, Sylvia, Georges, Guy, Korfi, Koorosh, Lechmann, Martin, Eigenmann, Miro Julian, Marbach, Daniel, Jamois, Candice, Lechner, Katharina, Krishnan, Sreenath M., Gaillard, Brenda, Marinho, Joana, Kronenberg, Sven, Kunz, Leo, Wilson, Sabine, Briner, Stefanie, Gebhardt, Samuel, Varol, Ahmet, Appelt, Birte, Nicolini, Valeria, Speziale, Dario, Bez, Miriam, Bommer, Esther, Eckmann, Jan, Hage, Carina, Limani, Florian, Jenni, Silvia, Schoenle, Anne, Le Clech, Marine, Vallier, Jean-Baptiste Pierre, Colombetti, Sara, Bacac, Marina, Gasser, Stephan, Klein, Christian, and Umaña, Pablo

Published
2024
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4. Single-cell analysis of structural variations and complex rearrangements with tri-channel processing

Author

Sanders, Ashley D., Meiers, Sascha, Ghareghani, Maryam, Porubsky, David, Jeong, Hyobin, van Vliet, M. Alexandra C. C., Rausch, Tobias, Richter-Pechańska, Paulina, Kunz, Joachim B., Jenni, Silvia, Bolognini, Davide, Longo, Gabriel M. C., Raeder, Benjamin, Kinanen, Venla, Zimmermann, Jürgen, Benes, Vladimir, Schrappe, Martin, Mardin, Balca R., Kulozik, Andreas E., Bornhauser, Beat, Bourquin, Jean-Pierre, Marschall, Tobias, and Korbel, Jan O.

Published
2020
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5. Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Author

Frismantas, Viktoras, Dobay, Maria Pamela, Rinaldi, Anna, Tchinda, Joelle, Dunn, Samuel H., Kunz, Joachim, Richter-Pechanska, Paulina, Marovca, Blerim, Pail, Orrin, Jenni, Silvia, Diaz-Flores, Ernesto, Chang, Bill H., Brown, Timothy J., Collins, Robert H., Uhrig, Sebastian, Balasubramanian, Gnana P., Bandapalli, Obul R., Higi, Salome, Eugster, Sabrina, Voegeli, Pamela, Delorenzi, Mauro, Cario, Gunnar, Loh, Mignon L., Schrappe, Martin, Stanulla, Martin, Kulozik, Andreas E., Muckenthaler, Martina U., Saha, Vaskar, Irving, Julie A., Meisel, Roland, Radimerski, Thomas, Von Stackelberg, Arend, Eckert, Cornelia, Tyner, Jeffrey W., Horvath, Peter, Bornhauser, Beat C., and Bourquin, Jean-Pierre

Published
2017
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6. Repurposing anthelmintic agents to eradicate resistant leukemia

Author

Mezzatesta, Caterina, Abduli, Liridon, Guinot, Anna, Eckert, Cornelia, Schewe, Denis, Zaliova, Marketa, Vinti, Luciana, Marovca, Blerim, Tsai, Yi-Chien, Jenni, Silvia, Aguade-Gorgorio, Julia, von Stackelberg, Arend, Schrappe, Martin, Locatelli, Franco, Stanulla, Martin, Cario, Gunnar, Bourquin, Jean-Pierre, and Bornhauser, Beat C.

Published
2020
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8. Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling

Author

Seyfried, Felix, Demir, Salih, Hörl, Rebecca Louise, Stirnweiß, Felix Uli, Ryan, Jeremy, Scheffold, Annika, Villalobos-Ortiz, Mariana, Boldrin, Elena, Zinngrebe, Julia, Enzenmüller, Stefanie, Jenni, Silvia, Tsai, Yi-Chien, Bornhauser, Beat, Fürstberger, Axel, Kraus, Johann Michael, Kestler, Hans Armin, Bourquin, Jean-Pierre, Stilgenbauer, Stephan, Letai, Anthony, Debatin, Klaus-Michael, and Meyer, Lüder Hinrich

Published
2019
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9. Supplementary Data from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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10. Figure S3 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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11. Supplementary Table 6 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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12. Supplementary Table 5 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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13. Supplementary Table 3 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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14. Supplementary Table 4 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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15. Supplementary Table 2 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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16. Supplementary Table 7 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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17. Supplementary Table 1 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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18. Supplementary Table 8 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, primary, Ignacimouttou, Cathy, primary, Panchal, Kunjal, primary, Diop, M'Boyba, primary, Jenni, Silvia, primary, Tsai, Yi-Chien, primary, Roos-Weil, Damien, primary, Aid, Zakia, primary, Prade, Nais, primary, Lagarde, Stephanie, primary, Plassard, Damien, primary, Pierron, Gaelle, primary, Daudigeos, Estelle, primary, Lecluse, Yann, primary, Droin, Nathalie, primary, Bornhauser, Beat C., primary, Cheung, Laurence C., primary, Crispino, John D., primary, Gaudry, Muriel, primary, Bernard, Olivier A., primary, Macintyre, Elizabeth, primary, Barin Bonnigal, Carole, primary, Kotecha, Rishi S., primary, Geoerger, Birgit, primary, Ballerini, Paola, primary, Bourquin, Jean-Pierre, primary, Delabesse, Eric, primary, Mercher, Thomas, primary, and Malinge, Sebastien, primary

Published
2023
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20. DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

Author

Bhansali, Rahul S., Rammohan, Malini, Lee, Paul, Laurent, Anouchka P., Wen, Qiang, Suraneni, Praveen, Yip, Bon Ham, Tsai, Yi-Chien, Jenni, Silvia, Bornhauser, Beat, Siret, Aurelie, Fruit, Corinne, Pacheco-Benichou, Alexandra, Harris, Ethan, Besson, Thierry, Thompson, Benjamin J., Goo, Young Ah, Hijiya, Nobuko, Vilenchik, Maria, Izraeli, Shai, Bourquin, Jean-Pierre, Malinge, Sebastien, and Crispino, John D.

Subjects
Physiological aspects, Development and progression, Genetic aspects, Health aspects, B cells -- Physiological aspects -- Health aspects, Protein kinases -- Genetic aspects -- Health aspects, Transcription factors -- Physiological aspects -- Health aspects, Acute lymphocytic leukemia -- Genetic aspects -- Development and progression, STAT3 -- Physiological aspects -- Health aspects
Abstract

Introduction B cell acute lymphoblastic leukemia (B-ALL) is the most commonly diagnosed pediatric cancer, with incidence peaking between the ages of 2 and 5 years (1). The success of multidrug [...], DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.

Published
2021
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21. RG6333 (CD19-CD28), a CD19-Targeted Affinity-Optimized CD28 Bispecific Antibody, Enhances and Prolongs the Anti-Tumor Activity of Glofitamab (CD20-TCB) in Preclinical Models

Author

Sam, Johannes, primary, Hofer, Thomas, additional, Kuettel, Christine, additional, Claus, Christina, additional, Herter, Sylvia, additional, Georges, Guy, additional, Thom, Jenny Tosca, additional, Kunz, Leo, additional, Gebhardt, Samuel, additional, Limani, Florian, additional, Briner, Stefanie, additional, Jenni, Silvia, additional, Schönle, Anne, additional, Le Clech, Marine, additional, Varol, Ahmet, additional, Bommer, Esther, additional, Appelt, Birte, additional, Colombetti, Sara, additional, Gasser, Stephan, additional, Bacac, Marina, additional, Klein, Christian, additional, and Umana, Pablo, additional

Published
2022
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22. In Vitro Drug Response Profiling in BCP- and T-ALL Primary Samples Adds a Robust Functional Layer Enabling Optimized Guidance of Individualized Therapy in Relapsed and Refractory Pediatric Acute Leukemia Patients

Author

Lissat, Andrej, primary, Maniotis, Despina, additional, Nosswitz, Michael, additional, Alten, Julia, additional, Jenni, Silvia, additional, Tsai, Yi-Chien, additional, Cario, Gunnar, additional, La Starza, Roberta, additional, Hrusak, Ondrej, additional, Kulozik, Andreas E., additional, Witt, Olaf, additional, Stanulla, Martin, additional, Schrappe, Martin, additional, Zwaan, Christian M., additional, Eckert, Cornelia, additional, von Stackelberg, Arend, additional, Baruchel, Andre, additional, Jacoby, Elad, additional, Karow, Axel, additional, Ceppi, Francesco, additional, Bornhauser, Beat, additional, and Bourquin, Jean-Pierre, additional

Published
2020
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23. Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P., primary, Siret, Aurélie, additional, Ignacimouttou, Cathy, additional, Panchal, Kunjal, additional, Diop, M'Boyba, additional, Jenni, Silvia, additional, Tsai, Yi-Chien, additional, Roos-Weil, Damien, additional, Aid, Zakia, additional, Prade, Nais, additional, Lagarde, Stephanie, additional, Plassard, Damien, additional, Pierron, Gaelle, additional, Daudigeos, Estelle, additional, Lecluse, Yann, additional, Droin, Nathalie, additional, Bornhauser, Beat C., additional, Cheung, Laurence C., additional, Crispino, John D., additional, Gaudry, Muriel, additional, Bernard, Olivier A., additional, Macintyre, Elizabeth, additional, Barin Bonnigal, Carole, additional, Kotecha, Rishi S., additional, Geoerger, Birgit, additional, Ballerini, Paola, additional, Bourquin, Jean-Pierre, additional, Delabesse, Eric, additional, Mercher, Thomas, additional, and Malinge, Sebastien, additional

Published
2020
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24. Repurposing anthelmintic agents to eradicate resistant leukemia

Author

Mezzatesta, Caterina; https://orcid.org/0000-0001-6643-466X, Abduli, Liridon, Guinot, Anna, Eckert, Cornelia, Schewe, Denis; https://orcid.org/0000-0002-1070-0217, Zaliova, Marketa; https://orcid.org/0000-0002-1639-7124, Vinti, Luciana, Marovca, Blerim, Tsai, Yi-Chien, Jenni, Silvia, Aguade-Gorgorio, Julia, von Stackelberg, Arend, Schrappe, Martin, Locatelli, Franco, Stanulla, Martin, Cario, Gunnar, Bourquin, Jean-Pierre, Bornhauser, Beat C; https://orcid.org/0000-0003-2890-3191, Mezzatesta, Caterina; https://orcid.org/0000-0001-6643-466X, Abduli, Liridon, Guinot, Anna, Eckert, Cornelia, Schewe, Denis; https://orcid.org/0000-0002-1070-0217, Zaliova, Marketa; https://orcid.org/0000-0002-1639-7124, Vinti, Luciana, Marovca, Blerim, Tsai, Yi-Chien, Jenni, Silvia, Aguade-Gorgorio, Julia, von Stackelberg, Arend, Schrappe, Martin, Locatelli, Franco, Stanulla, Martin, Cario, Gunnar, Bourquin, Jean-Pierre, and Bornhauser, Beat C; https://orcid.org/0000-0003-2890-3191

Abstract

Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC$_{50}$ values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.

Published
2020

25. Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Laurent, Anouchka P, Siret, Aurélie, Ignacimouttou, Cathy, Panchal, Kunjal, Diop, M'Boyba, Jenni, Silvia, Tsai, Yi-Chien, Roos-Weil, Damien; https://orcid.org/0000-0002-7767-755X, Aid, Zakia, Prade, Nais, Lagarde, Stephanie, Plassard, Damien, Pierron, Gaelle; https://orcid.org/0000-0002-2536-7680, Daudigeos, Estelle, Lecluse, Yann, Droin, Nathalie; https://orcid.org/0000-0002-6099-5324, Bornhauser, Beat C, Cheung, Laurence C; https://orcid.org/0000-0001-6298-5288, Crispino, John D; https://orcid.org/0000-0002-8182-8306, Gaudry, Muriel, Bernard, Olivier A, Macintyre, Elizabeth, Barin Bonnigal, Carole, Kotecha, Rishi S; https://orcid.org/0000-0003-1836-4075, Geoerger, Birgit; https://orcid.org/0000-0003-4361-3643, Ballerini, Paola, Bourquin, Jean-Pierre, Delabesse, Eric, Mercher, Thomas; https://orcid.org/0000-0003-1552-087X, Malinge, Sebastien; https://orcid.org/0000-0002-9533-7778, Laurent, Anouchka P, Siret, Aurélie, Ignacimouttou, Cathy, Panchal, Kunjal, Diop, M'Boyba, Jenni, Silvia, Tsai, Yi-Chien, Roos-Weil, Damien; https://orcid.org/0000-0002-7767-755X, Aid, Zakia, Prade, Nais, Lagarde, Stephanie, Plassard, Damien, Pierron, Gaelle; https://orcid.org/0000-0002-2536-7680, Daudigeos, Estelle, Lecluse, Yann, Droin, Nathalie; https://orcid.org/0000-0002-6099-5324, Bornhauser, Beat C, Cheung, Laurence C; https://orcid.org/0000-0001-6298-5288, Crispino, John D; https://orcid.org/0000-0002-8182-8306, Gaudry, Muriel, Bernard, Olivier A, Macintyre, Elizabeth, Barin Bonnigal, Carole, Kotecha, Rishi S; https://orcid.org/0000-0003-1836-4075, Geoerger, Birgit; https://orcid.org/0000-0003-4361-3643, Ballerini, Paola, Bourquin, Jean-Pierre, Delabesse, Eric, Mercher, Thomas; https://orcid.org/0000-0003-1552-087X, and Malinge, Sebastien; https://orcid.org/0000-0002-9533-7778

Abstract

PURPOSE Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL. EXPERIMENTAL DESIGN To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents. RESULTS Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRAS$^{G12D}$ functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine. CONCLUSIONS Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.

Published
2020

27. Single-cell analysis of structural variations and complex rearrangements with tri-channel processing

Author

Sanders, Ashley D., primary, Meiers, Sascha, additional, Ghareghani, Maryam, additional, Porubsky, David, additional, Jeong, Hyobin, additional, van Vliet, M. Alexandra C. C., additional, Rausch, Tobias, additional, Richter-Pechańska, Paulina, additional, Kunz, Joachim B., additional, Jenni, Silvia, additional, Bolognini, Davide, additional, Longo, Gabriel M. C., additional, Raeder, Benjamin, additional, Kinanen, Venla, additional, Zimmermann, Jürgen, additional, Benes, Vladimir, additional, Schrappe, Martin, additional, Mardin, Balca R., additional, Kulozik, Andreas E., additional, Bornhauser, Beat, additional, Bourquin, Jean-Pierre, additional, Marschall, Tobias, additional, and Korbel, Jan O., additional

Published
2019
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28. The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability

Author

Huang, Yun, primary, Mouttet, Brice, additional, Warnatz, Hans-Jörg, additional, Risch, Thomas, additional, Rietmann, Fabian, additional, Frommelt, Fabian, additional, Ngo, Quy A., additional, Dobay, Maria Pamela, additional, Marovca, Blerim, additional, Jenni, Silvia, additional, Tsai, Yi-Chien, additional, Matzk, Sören, additional, Amstislavskiy, Vyacheslav, additional, Schrappe, Martin, additional, Stanulla, Martin, additional, Gstaiger, Matthias, additional, Bornhauser, Beat, additional, Yaspo, Marie-Laure, additional, and Bourquin, Jean-Pierre, additional

Published
2019
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29. Single cell tri-channel-processing reveals structural variation landscapes and complex rearrangement processes

Author

Sanders, Ashley D., primary, Meiers, Sascha, additional, Ghareghani, Maryam, additional, Porubsky, David, additional, Jeong, Hyobin, additional, van Vliet, M. Alexandra C.C., additional, Rausch, Tobias, additional, Richter-Pechańska, Paulina, additional, Kunz, Joachim B., additional, Jenni, Silvia, additional, Raeder, Benjamin, additional, Kinanen, Venla, additional, Zimmermann, Jürgen, additional, Benes, Vladimir, additional, Schrappe, Martin, additional, Mardin, Balca R., additional, Kulozik, Andreas, additional, Bornhauser, Beat, additional, Bourquin, Jean-Pierre, additional, Marschall, Tobias, additional, and Korbel, Jan O., additional

Published
2019
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31. Abstract 4796: EG-011 is a novel small molecule within vitroandin vivoanti-tumor activity against lymphoma

Author

Gaudio, Eugenio, primary, Spriano, Filippo, additional, Tarantelli, Chiara, additional, Guala, Matilde, additional, Riveiro, Eugenia, additional, Golino, Gaetanina, additional, Lupia, Antonio, additional, Costa, Giosuè, additional, Rocca, Roberta, additional, Cascione, Luciano, additional, Jenni, Silvia, additional, Tsai, Yi-Chien, additional, Bornhauser, Beat, additional, Alcaro, Stefano, additional, Paduano, Francesco, additional, Trapasso, Francesco, additional, Zucca, Emanuele, additional, Stathis, Anastasios, additional, Pazzi, Natalina, additional, Cavalli, Franco, additional, and Bertoni, Francesco, additional

Published
2019
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32. Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7

Author

McComb, Scott; https://orcid.org/0000-0002-4616-7864, Chan, Pik Ki; https://orcid.org/0000-0001-5290-7825, Guinot, Anna; https://orcid.org/0000-0002-9933-8356, Hartmannsdottir, Holmfridur; https://orcid.org/0000-0002-1952-0714, Jenni, Silvia, Dobay, Maria Pamela, Bourquin, Jean-Pierre, Bornhauser, Beat C; https://orcid.org/0000-0003-2890-3191, McComb, Scott; https://orcid.org/0000-0002-4616-7864, Chan, Pik Ki; https://orcid.org/0000-0001-5290-7825, Guinot, Anna; https://orcid.org/0000-0002-9933-8356, Hartmannsdottir, Holmfridur; https://orcid.org/0000-0002-1952-0714, Jenni, Silvia, Dobay, Maria Pamela, Bourquin, Jean-Pierre, and Bornhauser, Beat C; https://orcid.org/0000-0003-2890-3191

Abstract

Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondrial depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.

Published
2019

35. Pre-clinical evaluation of second generation PIM inhibitors for the treatment of T-cell acute lymphoblastic leukemia and lymphoma

Author

De Smedt, Renate, primary, Peirs, Sofie, additional, Morscio, Julie, additional, Matthijssens, Filip, additional, Roels, Juliette, additional, Reunes, Lindy, additional, Lintermans, Beatrice, additional, Goossens, Steven, additional, Lammens, Tim, additional, Van Roy, Nadine, additional, Touzart, Aurore, additional, Jenni, Silvia, additional, Tsai, Yi-Chien, additional, Lovisa, Federica, additional, Mussolin, Lara, additional, Serafin, Valentina, additional, Van Nieuwerburgh, Filip, additional, Deforce, Dieter, additional, Uyttebroeck, Anne, additional, Tousseyn, Thomas, additional, Burkhardt, Birgit, additional, Klapper, Wolfram, additional, De Moerloose, Barbara, additional, Benoit, Yves, additional, Macintyre, Elizabeth, additional, Bourquin, Jean-Pierre, additional, Basso, Giuseppe, additional, Accordi, Benedetta, additional, Bornhauser, Beat, additional, Meijerink, Jules, additional, Vandenberghe, Peter, additional, and Van Vlierberghe, Pieter, additional

Published
2018
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36. Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Frismantas, Viktoras, Dobay, Maria Pamela, Rinaldi, Anna, Tchinda, Joelle, Dunn, Samuel H., Kunz, Joachim, Richter-Pechanska, Paulina, Marovca, Blerim, Pail, Orrin, Jenni, Silvia, Diaz-Flores, Ernesto, Chang, Bill H., Brown, Timothy J., Collins, Robert H., Uhrig, Sebastian, Balasubramanian, Gnana P., Bandapalli, Obul R., Higi, Salome, Eugster, Sabrina, Voegeli, Pamela, Delorenzi, Mauro, Cario, Gunnar, Loh, Mignon L., Schrappe, Martin, Stanulla, Martin, Kulozik, Andreas E., Muckenthaler, Martina U., Saha, Vaskar, Irving, Julie A., Meisel, Roland, Radimerski, Thomas, Von Stackelberg, Arend, Eckert, Cornelia, Tyner, Jeffrey W., Horvath, Peter, Bornhauser, Beat C., Bourquin, Jean-Pierre, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Frismantas, Viktoras, Dobay, Maria Pamela, Rinaldi, Anna, Tchinda, Joelle, Dunn, Samuel H., Kunz, Joachim, Richter-Pechanska, Paulina, Marovca, Blerim, Pail, Orrin, Jenni, Silvia, Diaz-Flores, Ernesto, Chang, Bill H., Brown, Timothy J., Collins, Robert H., Uhrig, Sebastian, Balasubramanian, Gnana P., Bandapalli, Obul R., Higi, Salome, Eugster, Sabrina, Voegeli, Pamela, Delorenzi, Mauro, Cario, Gunnar, Loh, Mignon L., Schrappe, Martin, Stanulla, Martin, Kulozik, Andreas E., Muckenthaler, Martina U., Saha, Vaskar, Irving, Julie A., Meisel, Roland, Radimerski, Thomas, Von Stackelberg, Arend, Eckert, Cornelia, Tyner, Jeffrey W., Horvath, Peter, Bornhauser, Beat C., and Bourquin, Jean-Pierre

Abstract

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.

Published
2017

37. 18F-5-Fluoroaminosuberic Acid as a Potential Tracer to Gauge Oxidative Stress in Breast Cancer Models

Author

Yang, Hua, primary, Jenni, Silvia, additional, Colovic, Milena, additional, Merkens, Helen, additional, Poleschuk, Carlee, additional, Rodrigo, Isabel, additional, Miao, Qing, additional, Johnson, Bruce F., additional, Rishel, Michael J., additional, Sossi, Vesna, additional, Webster, Jack M., additional, Bénard, François, additional, and Schaffer, Paul, additional

Published
2016
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39. Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel–Chelator Complex on Biodistribution and Tumor Uptake

Author

Zhang, Zhengxing, primary, Amouroux, Guillaume, additional, Pan, Jinhe, additional, Jenni, Silvia, additional, Zeisler, Jutta, additional, Zhang, Chengcheng, additional, Liu, Zhibo, additional, Perrin, David M., additional, Bénard, François, additional, and Lin, Kuo-Shyan, additional

Published
2016
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48. In VitroDrug Response Profiling in BCP- and T-ALL Primary Samples Adds a Robust Functional Layer Enabling Optimized Guidance of Individualized Therapy in Relapsed and Refractory Pediatric Acute Leukemia Patients

Author

Lissat, Andrej, Maniotis, Despina, Nosswitz, Michael, Alten, Julia, Jenni, Silvia, Tsai, Yi-Chien, Cario, Gunnar, La Starza, Roberta, Hrusak, Ondrej, Kulozik, Andreas E., Witt, Olaf, Stanulla, Martin, Schrappe, Martin, Zwaan, Christian M., Eckert, Cornelia, von Stackelberg, Arend, Baruchel, Andre, Jacoby, Elad, Karow, Axel, Ceppi, Francesco, Bornhauser, Beat, and Bourquin, Jean-Pierre

Published
2020
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49. In Vivo Radioimaging of Bradykinin Receptor B1, a Widely Overexpressed Molecule in Human Cancer.

Author

Kuo-Shyan Lin, Jinhe Pan, Amouroux, Guillaume, Turashvili, Gulisa, Mesak, Felix, Hundal-Jabal, Navjit, Pourghiasian, Maral, Lau, Joseph, Jenni, Silvia, Aparicio, Samuel, and Bénard, François

Subjects
*BRADYKININ, *BRADYKININ receptors, *CANCER research, *IMAGING of cancer, *KALLIDIN
Abstract

The bradykinin receptor B1R is overexpressed in many human cancers where it might be used as a general target for cancer imaging. In this study, we evaluated the feasibility of using radiolabeled kallidin derivatives to visualize B1R expression in a preclinical model of B1R-positive tumors. Three synthetic derivatives were evaluated in vitro and in vivo for receptor binding and their ability to visualize tumors by PET. Enalaprilat and phosphoramidon were used to evaluate the impact of peptidases on tumor visualization. While we found that radiolabeled peptides based on the native kallidin sequence were ineffective at visualizing B1R-positive tumors, peptidase inhibition with phosphoramidon greatly enhanced B1R visualization in vivo. Two stabilized derivatives incorporating unnatural amino acids (68Ga-SH01078 and 68Ga-P03034) maintained receptor-binding affinities that were effective, allowing excellent tumor visualization, minimal accumulation in normal tissues, and rapid renal clearance. Tumor uptake was blocked in the presence of excess competitor, confirming that the specificity of tumor accumulation was receptor mediated. Our results offer a preclinical proof of concept for noninvasive B1R detection by PET imaging as a general tool to visualize many human cancers. [ABSTRACT FROM AUTHOR]

Published
2015
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50. Pre-clinical evaluation of second generation PIM inhibitors for the treatment of T-cell acute lymphoblastic leukemia and lymphoma.

Author

De Smedt R, Peirs S, Morscio J, Matthijssens F, Roels J, Reunes L, Lintermans B, Goossens S, Lammens T, Van Roy N, Touzart A, Jenni S, Tsai YC, Lovisa F, Mussolin L, Serafin V, Van Nieuwerburgh F, Deforce D, Uyttebroeck A, Tousseyn T, Burkhardt B, Klapper W, De Moerloose B, Benoit Y, Macintyre E, Bourquin JP, Basso G, Accordi B, Bornhauser B, Meijerink J, Vandenberghe P, and Van Vlierberghe P

Subjects
Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma enzymology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Proto-Oncogene Proteins c-pim-1 metabolism
Published
2019
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