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153 results on '"Hüllein, Jennifer"'

1. NCT/DKFZ MASTER handbook of interpreting whole-genome, transcriptome, and methylome data for precision oncology

Author

Mock, Andreas, Teleanu, Maria-Veronica, Kreutzfeldt, Simon, Heilig, Christoph E., Hüllein, Jennifer, Möhrmann, Lino, Jahn, Arne, Hanf, Dorothea, Kerle, Irina A., Singh, Hans Martin, Hutter, Barbara, Uhrig, Sebastian, Fröhlich, Martina, Neumann, Olaf, Hartig, Andreas, Brückmann, Sascha, Hirsch, Steffen, Grund, Kerstin, Dikow, Nicola, Lipka, Daniel B., Renner, Marcus, Bhatti, Irfan Ahmed, Apostolidis, Leonidas, Schlenk, Richard F., Schaaf, Christian P., Stenzinger, Albrecht, Schröck, Evelin, Hübschmann, Daniel, Heining, Christoph, Horak, Peter, Glimm, Hanno, and Fröhling, Stefan

Published
2023
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2. aRgus: Multilevel visualization of non-synonymous single nucleotide variants & advanced pathogenicity score modeling for genetic vulnerability assessment

Author

Schröter, Julian, Dattner, Tal, Hüllein, Jennifer, Jayme, Alejandra, Heuveline, Vincent, Hoffmann, Georg F., Kölker, Stefan, Lenz, Dominic, Opladen, Thomas, Popp, Bernt, Schaaf, Christian P., Staufner, Christian, Syrbe, Steffen, Uhrig, Sebastian, Hübschmann, Daniel, and Brennenstuhl, Heiko

Published
2023
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3. Fibroblast Activation Protein α-Directed Imaging and Therapy of Solitary Fibrous Tumor.

Author

Hamacher, Rainer, Pabst, Kim M., Cheung, Phyllis F., Heilig, Christoph E., Hüllein, Jennifer, Liffers, Sven-Thorsten, Borchert, Sabrina, Costa, Pedro Fragoso, Schaarschmidt, Benedikt M., Kessler, Lukas, Miera, Monika A., Droste, Margret, Akbulut, Merve, Falkenhorst, Johanna, Zarrad, Fadi, Kostbade, Karina, Mavroeidi, Ilektra A., Glimm, Hanno, Umutlu, Lale, and Schuler, Martin

Published
2024
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4. 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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5. Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in HCC

Author

Scherr, Anna-Lena, primary, Nader, Luisa, additional, Xu, Kaiyu, additional, Elssner, Christin, additional, Ridder, Dirk A., additional, Nichetti, Federico, additional, Mastel, Manuel, additional, Fritzsche, Sarah, additional, Kelmendi, Eblina, additional, Schmitt, Nathalie, additional, Hoffmeister-Wittmann, Paula, additional, Weiler, Sofia M. E., additional, Korell, Felix, additional, Albrecht, Thomas, additional, Schwab, Maximilian, additional, Isele, Hanna, additional, Kessler, Annika, additional, Hüllein, Jennifer, additional, Seretny, Agnieszka, additional, Ye, Liangtao, additional, Urbanik, Toni, additional, Welte, Stefan, additional, Leblond, Anne-Laure, additional, Heilig, Christoph E., additional, Rahbari, Mohammad, additional, Ali, Adnan, additional, Gallage, Suchira, additional, Lenoir, Bénédicte, additional, Wilhelm, Nina, additional, Gärtner, Ulrike, additional, Ogrodnik, Simon J., additional, Springfeld, Christoph, additional, Tschaharganeh, Darjus, additional, Fröhling, Stefan, additional, Longerich, Thomas, additional, Schulze-Bergkamen, Henning, additional, Jäger, Dirk, additional, Brandl, Lydia, additional, Schirmacher, Peter, additional, Straub, Beate K., additional, Weber, Achim, additional, De Toni, Enrico N., additional, Goeppert, Benjamin, additional, Heikenwalder, Mathias, additional, Jackstadt, Rene, additional, Roessler, Stephanie, additional, Breuhahn, Kai, additional, and Köhler, Bruno C., additional

Published
2023
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6. Evolution of DNA Methylation Is Linked to Genetic Aberrations in Chronic Lymphocytic Leukemia

Author

Oakes, Christopher C, Claus, Rainer, Gu, Lei, Assenov, Yassen, Hüllein, Jennifer, Zucknick, Manuela, Bieg, Matthias, Brocks, David, Bogatyrova, Olga, Schmidt, Christopher R, Rassenti, Laura, Kipps, Thomas J, Mertens, Daniel, Lichter, Peter, Döhner, Hartmut, Stilgenbauer, Stephan, Byrd, John C, Zenz, Thorsten, and Plass, Christoph

Subjects
Rare Diseases, Genetic Testing, Genetics, Cancer, Lymphoma, Human Genome, Hematology, Good Health and Well Being, Aged, Chromosomes, Human, CpG Islands, DNA Methylation, Disease Progression, Epigenesis, Genetic, Female, Gene Expression Regulation, Leukemic, Genetic Heterogeneity, Genome, Human, Genomic Instability, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Oncology and Carcinogenesis
Abstract

Although clonal selection by genetic driver aberrations in cancer is well documented, the ability of epigenetic alterations to promote tumor evolution is undefined. We used 450k arrays and next-generation sequencing to evaluate intratumor heterogeneity and evolution of DNA methylation and genetic aberrations in chronic lymphocytic leukemia (CLL). CLL cases exhibit vast interpatient differences in intratumor methylation heterogeneity, with genetically clonal cases maintaining low methylation heterogeneity and up to 10% of total CpGs in a monoallelically methylated state. Increasing methylation heterogeneity correlates with advanced genetic subclonal complexity. Selection of novel DNA methylation patterns is observed only in cases that undergo genetic evolution, and independent genetic evolution is uncommon and is restricted to low-risk alterations. These results reveal that although evolution of DNA methylation occurs in high-risk, clinically progressive cases, positive selection of novel methylation patterns entails coevolution of genetic alteration(s) in CLL.

Published
2014

9. Abstract 926: Genomics-based personalized oncology of advanced thymic epithelial tumors

Author

Möhrmann, Lino, primary, Rostock, Lysann, additional, Oleś, Małgorzata, additional, Jahn, Arne, additional, Arlt, Marie, additional, Paramasivam, Nagarajan, additional, Jöhrens, Korinna, additional, Rupp, Luise, additional, Schmitz, Marc, additional, Richter, Daniela, additional, Uhrig, Sebastian, additional, Fröhlich, Martina, additional, Hutter, Barbara, additional, Hüllein, Jennifer, additional, Wolf, Elena E., additional, Hanf, Dorothea, additional, Gieldon, Laura, additional, Kreutzfeldt, Simon, additional, Heilig, Christoph E., additional, Teleanu, Veronica, additional, Lipka, Daniel B., additional, Mock, Andreas, additional, Jelas, Ivan, additional, Rieke, Damian T., additional, Wiesweg, Marcel, additional, Boerries, Melanie, additional, Illert, Anna L., additional, Desuki, Alexander, additional, Kindler, Thomas, additional, Krackhardt, Angela M., additional, Westphalen, C. Benedikt, additional, Grosch, Heidrun, additional, Apostolidis, Leonidas, additional, Stenzinger, Albrecht, additional, Kerle, Irina A., additional, Heining, Christoph, additional, Hübschmann, Daniel, additional, Schröck, Evelin, additional, Fröhling, Stefan, additional, and Glimm, Hanno, additional

Published
2023
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10. Data from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Author

Horak, Peter, primary, Heining, Christoph, primary, Kreutzfeldt, Simon, primary, Hutter, Barbara, primary, Mock, Andreas, primary, Hüllein, Jennifer, primary, Fröhlich, Martina, primary, Uhrig, Sebastian, primary, Jahn, Arne, primary, Rump, Andreas, primary, Gieldon, Laura, primary, Möhrmann, Lino, primary, Hanf, Dorothea, primary, Teleanu, Veronica, primary, Heilig, Christoph E., primary, Lipka, Daniel B., primary, Allgäuer, Michael, primary, Ruhnke, Leo, primary, Laßmann, Andreas, primary, Endris, Volker, primary, Neumann, Olaf, primary, Penzel, Roland, primary, Beck, Katja, primary, Richter, Daniela, primary, Winter, Ulrike, primary, Wolf, Stephan, primary, Pfütze, Katrin, primary, Geörg, Christina, primary, Meißburger, Bettina, primary, Buchhalter, Ivo, primary, Augustin, Marinela, primary, Aulitzky, Walter E., primary, Hohenberger, Peter, primary, Kroiss, Matthias, primary, Schirmacher, Peter, primary, Schlenk, Richard F., primary, Keilholz, Ulrich, primary, Klauschen, Frederick, primary, Folprecht, Gunnar, primary, Bauer, Sebastian, primary, Siveke, Jens Thomas, primary, Brandts, Christian H., primary, Kindler, Thomas, primary, Boerries, Melanie, primary, Illert, Anna L., primary, von Bubnoff, Nikolas, primary, Jost, Philipp J., primary, Spiekermann, Karsten, primary, Bitzer, Michael, primary, Schulze-Osthoff, Klaus, primary, von Kalle, Christof, primary, Klink, Barbara, primary, Brors, Benedikt, primary, Stenzinger, Albrecht, primary, Schröck, Evelin, primary, Hübschmann, Daniel, primary, Weichert, Wilko, primary, Glimm, Hanno, primary, and Fröhling, Stefan, primary

Published
2023
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11. Data from Evolution of DNA Methylation Is Linked to Genetic Aberrations in Chronic Lymphocytic Leukemia

Author

Oakes, Christopher C., primary, Claus, Rainer, primary, Gu, Lei, primary, Assenov, Yassen, primary, Hüllein, Jennifer, primary, Zucknick, Manuela, primary, Bieg, Matthias, primary, Brocks, David, primary, Bogatyrova, Olga, primary, Schmidt, Christopher R., primary, Rassenti, Laura, primary, Kipps, Thomas J., primary, Mertens, Daniel, primary, Lichter, Peter, primary, Döhner, Hartmut, primary, Stilgenbauer, Stephan, primary, Byrd, John C., primary, Zenz, Thorsten, primary, and Plass, Christoph, primary

Published
2023
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12. Supplementary Tables S1-S7 from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Author

Horak, Peter, primary, Heining, Christoph, primary, Kreutzfeldt, Simon, primary, Hutter, Barbara, primary, Mock, Andreas, primary, Hüllein, Jennifer, primary, Fröhlich, Martina, primary, Uhrig, Sebastian, primary, Jahn, Arne, primary, Rump, Andreas, primary, Gieldon, Laura, primary, Möhrmann, Lino, primary, Hanf, Dorothea, primary, Teleanu, Veronica, primary, Heilig, Christoph E., primary, Lipka, Daniel B., primary, Allgäuer, Michael, primary, Ruhnke, Leo, primary, Laßmann, Andreas, primary, Endris, Volker, primary, Neumann, Olaf, primary, Penzel, Roland, primary, Beck, Katja, primary, Richter, Daniela, primary, Winter, Ulrike, primary, Wolf, Stephan, primary, Pfütze, Katrin, primary, Geörg, Christina, primary, Meißburger, Bettina, primary, Buchhalter, Ivo, primary, Augustin, Marinela, primary, Aulitzky, Walter E., primary, Hohenberger, Peter, primary, Kroiss, Matthias, primary, Schirmacher, Peter, primary, Schlenk, Richard F., primary, Keilholz, Ulrich, primary, Klauschen, Frederick, primary, Folprecht, Gunnar, primary, Bauer, Sebastian, primary, Siveke, Jens Thomas, primary, Brandts, Christian H., primary, Kindler, Thomas, primary, Boerries, Melanie, primary, Illert, Anna L., primary, von Bubnoff, Nikolas, primary, Jost, Philipp J., primary, Spiekermann, Karsten, primary, Bitzer, Michael, primary, Schulze-Osthoff, Klaus, primary, von Kalle, Christof, primary, Klink, Barbara, primary, Brors, Benedikt, primary, Stenzinger, Albrecht, primary, Schröck, Evelin, primary, Hübschmann, Daniel, primary, Weichert, Wilko, primary, Glimm, Hanno, primary, and Fröhling, Stefan, primary

Published
2023
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13. Supplementary Figures 1-10 from Evolution of DNA Methylation Is Linked to Genetic Aberrations in Chronic Lymphocytic Leukemia

Author

Oakes, Christopher C., primary, Claus, Rainer, primary, Gu, Lei, primary, Assenov, Yassen, primary, Hüllein, Jennifer, primary, Zucknick, Manuela, primary, Bieg, Matthias, primary, Brocks, David, primary, Bogatyrova, Olga, primary, Schmidt, Christopher R., primary, Rassenti, Laura, primary, Kipps, Thomas J., primary, Mertens, Daniel, primary, Lichter, Peter, primary, Döhner, Hartmut, primary, Stilgenbauer, Stephan, primary, Byrd, John C., primary, Zenz, Thorsten, primary, and Plass, Christoph, primary

Published
2023
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14. Supplementary Table 2 from Evolution of DNA Methylation Is Linked to Genetic Aberrations in Chronic Lymphocytic Leukemia

Author

Oakes, Christopher C., primary, Claus, Rainer, primary, Gu, Lei, primary, Assenov, Yassen, primary, Hüllein, Jennifer, primary, Zucknick, Manuela, primary, Bieg, Matthias, primary, Brocks, David, primary, Bogatyrova, Olga, primary, Schmidt, Christopher R., primary, Rassenti, Laura, primary, Kipps, Thomas J., primary, Mertens, Daniel, primary, Lichter, Peter, primary, Döhner, Hartmut, primary, Stilgenbauer, Stephan, primary, Byrd, John C., primary, Zenz, Thorsten, primary, and Plass, Christoph, primary

Published
2023
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15. Supplementary Table 1 from Evolution of DNA Methylation Is Linked to Genetic Aberrations in Chronic Lymphocytic Leukemia

Author

Oakes, Christopher C., primary, Claus, Rainer, primary, Gu, Lei, primary, Assenov, Yassen, primary, Hüllein, Jennifer, primary, Zucknick, Manuela, primary, Bieg, Matthias, primary, Brocks, David, primary, Bogatyrova, Olga, primary, Schmidt, Christopher R., primary, Rassenti, Laura, primary, Kipps, Thomas J., primary, Mertens, Daniel, primary, Lichter, Peter, primary, Döhner, Hartmut, primary, Stilgenbauer, Stephan, primary, Byrd, John C., primary, Zenz, Thorsten, primary, and Plass, Christoph, primary

Published
2023
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16. Supplementary Figures S1-S10 from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Author

Horak, Peter, primary, Heining, Christoph, primary, Kreutzfeldt, Simon, primary, Hutter, Barbara, primary, Mock, Andreas, primary, Hüllein, Jennifer, primary, Fröhlich, Martina, primary, Uhrig, Sebastian, primary, Jahn, Arne, primary, Rump, Andreas, primary, Gieldon, Laura, primary, Möhrmann, Lino, primary, Hanf, Dorothea, primary, Teleanu, Veronica, primary, Heilig, Christoph E., primary, Lipka, Daniel B., primary, Allgäuer, Michael, primary, Ruhnke, Leo, primary, Laßmann, Andreas, primary, Endris, Volker, primary, Neumann, Olaf, primary, Penzel, Roland, primary, Beck, Katja, primary, Richter, Daniela, primary, Winter, Ulrike, primary, Wolf, Stephan, primary, Pfütze, Katrin, primary, Geörg, Christina, primary, Meißburger, Bettina, primary, Buchhalter, Ivo, primary, Augustin, Marinela, primary, Aulitzky, Walter E., primary, Hohenberger, Peter, primary, Kroiss, Matthias, primary, Schirmacher, Peter, primary, Schlenk, Richard F., primary, Keilholz, Ulrich, primary, Klauschen, Frederick, primary, Folprecht, Gunnar, primary, Bauer, Sebastian, primary, Siveke, Jens Thomas, primary, Brandts, Christian H., primary, Kindler, Thomas, primary, Boerries, Melanie, primary, Illert, Anna L., primary, von Bubnoff, Nikolas, primary, Jost, Philipp J., primary, Spiekermann, Karsten, primary, Bitzer, Michael, primary, Schulze-Osthoff, Klaus, primary, von Kalle, Christof, primary, Klink, Barbara, primary, Brors, Benedikt, primary, Stenzinger, Albrecht, primary, Schröck, Evelin, primary, Hübschmann, Daniel, primary, Weichert, Wilko, primary, Glimm, Hanno, primary, and Fröhling, Stefan, primary

Published
2023
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17. Supplementary Methods from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Author

Horak, Peter, primary, Heining, Christoph, primary, Kreutzfeldt, Simon, primary, Hutter, Barbara, primary, Mock, Andreas, primary, Hüllein, Jennifer, primary, Fröhlich, Martina, primary, Uhrig, Sebastian, primary, Jahn, Arne, primary, Rump, Andreas, primary, Gieldon, Laura, primary, Möhrmann, Lino, primary, Hanf, Dorothea, primary, Teleanu, Veronica, primary, Heilig, Christoph E., primary, Lipka, Daniel B., primary, Allgäuer, Michael, primary, Ruhnke, Leo, primary, Laßmann, Andreas, primary, Endris, Volker, primary, Neumann, Olaf, primary, Penzel, Roland, primary, Beck, Katja, primary, Richter, Daniela, primary, Winter, Ulrike, primary, Wolf, Stephan, primary, Pfütze, Katrin, primary, Geörg, Christina, primary, Meißburger, Bettina, primary, Buchhalter, Ivo, primary, Augustin, Marinela, primary, Aulitzky, Walter E., primary, Hohenberger, Peter, primary, Kroiss, Matthias, primary, Schirmacher, Peter, primary, Schlenk, Richard F., primary, Keilholz, Ulrich, primary, Klauschen, Frederick, primary, Folprecht, Gunnar, primary, Bauer, Sebastian, primary, Siveke, Jens Thomas, primary, Brandts, Christian H., primary, Kindler, Thomas, primary, Boerries, Melanie, primary, Illert, Anna L., primary, von Bubnoff, Nikolas, primary, Jost, Philipp J., primary, Spiekermann, Karsten, primary, Bitzer, Michael, primary, Schulze-Osthoff, Klaus, primary, von Kalle, Christof, primary, Klink, Barbara, primary, Brors, Benedikt, primary, Stenzinger, Albrecht, primary, Schröck, Evelin, primary, Hübschmann, Daniel, primary, Weichert, Wilko, primary, Glimm, Hanno, primary, and Fröhling, Stefan, primary

Published
2023
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18. Table S3 from MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma

Author

Hüllein, Jennifer, primary, Słabicki, Mikołaj, primary, Rosolowski, Maciej, primary, Jethwa, Alexander, primary, Habringer, Stefan, primary, Tomska, Katarzyna, primary, Kurilov, Roma, primary, Lu, Junyan, primary, Scheinost, Sebastian, primary, Wagener, Rabea, primary, Huang, Zhiqin, primary, Lukas, Marina, primary, Yavorska, Olena, primary, Helfrich, Hanne, primary, Scholtysik, René, primary, Bonneau, Kyle, primary, Tedesco, Donato, primary, Küppers, Ralf, primary, Klapper, Wolfram, primary, Pott, Christiane, primary, Stilgenbauer, Stephan, primary, Burkhardt, Birgit, primary, Löffler, Markus, primary, Trümper, Lorenz H., primary, Hummel, Michael, primary, Brors, Benedikt, primary, Zapatka, Marc, primary, Siebert, Reiner, primary, Kreuz, Markus, primary, Keller, Ulrich, primary, Huber, Wolfgang, primary, and Zenz, Thorsten, primary

Published
2023
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19. Table S2, Table S4, Table S6, Figure S1, Figure S2, Figure S3, Figure S4, Figure S5, Figure S6, Supplementary Methods from MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma

Author

Hüllein, Jennifer, primary, Słabicki, Mikołaj, primary, Rosolowski, Maciej, primary, Jethwa, Alexander, primary, Habringer, Stefan, primary, Tomska, Katarzyna, primary, Kurilov, Roma, primary, Lu, Junyan, primary, Scheinost, Sebastian, primary, Wagener, Rabea, primary, Huang, Zhiqin, primary, Lukas, Marina, primary, Yavorska, Olena, primary, Helfrich, Hanne, primary, Scholtysik, René, primary, Bonneau, Kyle, primary, Tedesco, Donato, primary, Küppers, Ralf, primary, Klapper, Wolfram, primary, Pott, Christiane, primary, Stilgenbauer, Stephan, primary, Burkhardt, Birgit, primary, Löffler, Markus, primary, Trümper, Lorenz H., primary, Hummel, Michael, primary, Brors, Benedikt, primary, Zapatka, Marc, primary, Siebert, Reiner, primary, Kreuz, Markus, primary, Keller, Ulrich, primary, Huber, Wolfgang, primary, and Zenz, Thorsten, primary

Published
2023
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20. Data from MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma

Author

Hüllein, Jennifer, primary, Słabicki, Mikołaj, primary, Rosolowski, Maciej, primary, Jethwa, Alexander, primary, Habringer, Stefan, primary, Tomska, Katarzyna, primary, Kurilov, Roma, primary, Lu, Junyan, primary, Scheinost, Sebastian, primary, Wagener, Rabea, primary, Huang, Zhiqin, primary, Lukas, Marina, primary, Yavorska, Olena, primary, Helfrich, Hanne, primary, Scholtysik, René, primary, Bonneau, Kyle, primary, Tedesco, Donato, primary, Küppers, Ralf, primary, Klapper, Wolfram, primary, Pott, Christiane, primary, Stilgenbauer, Stephan, primary, Burkhardt, Birgit, primary, Löffler, Markus, primary, Trümper, Lorenz H., primary, Hummel, Michael, primary, Brors, Benedikt, primary, Zapatka, Marc, primary, Siebert, Reiner, primary, Kreuz, Markus, primary, Keller, Ulrich, primary, Huber, Wolfgang, primary, and Zenz, Thorsten, primary

Published
2023
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21. Subgroup-specific gene expression profiles and mixed epistasis in chronic lymphocytic leukemia

Author

Lütge, Almut, Lu, Junyan, Hüllein, Jennifer, Walther, Tatjana, Sellner, Leopold, Wu, Bian, Rosenquist, Richard, Oakes, Christopher C, Dietrich, Sascha, Huber, Wolfgang, Zenz, Thorsten, Lütge, Almut, Lu, Junyan, Hüllein, Jennifer, Walther, Tatjana, Sellner, Leopold, Wu, Bian, Rosenquist, Richard, Oakes, Christopher C, Dietrich, Sascha, Huber, Wolfgang, and Zenz, Thorsten

Abstract

Understanding the molecular and phenotypic heterogeneity of cancer is a prerequisite for effective treatment. For chronic lymphocytic leukemia (CLL), recurrent genetic driver events have been extensively cataloged, but this does not suffice to explain the disease's diverse course. Here, we performed RNA sequencing on 184 CLL patient samples. Unsupervised analysis revealed two major, orthogonal axes of gene expression variation: the first one represented the mutational status of the immunoglobulin heavy variable (IGHV) genes, and concomitantly, the three-group stratification of CLL by global DNA methylation. The second axis aligned with trisomy 12 status and affected chemokine, MAPK and mTOR signaling. We discovered non-additive effects (epistasis) of IGHV mutation status and trisomy 12 on multiple phenotypes, including the expression of 893 genes. Multiple types of epistasis were observed, including synergy, buffering, suppression and inversion, suggesting that molecular understanding of disease heterogeneity requires studying such genetic events not only individually but in combination. We detected strong differentially expressed gene signatures associated with major gene mutations and copy number aberrations including SF3B1, BRAF and TP53, as well as del(17)(p13), del(13)(q14) and del(11)(q22.3) beyond dosage effect. Our study reveals previously underappreciated gene expression signatures for the major molecular subtypes in CLL and the presence of epistasis between them.

Published
2023

22. BRAF inhibition in hairy cell leukemia with low-dose vemurafenib

Author

Dietrich, Sascha, Pircher, Andreas, Endris, Volker, Peyrade, Frédéric, Wendtner, Clemens-Martin, Follows, George A., Hüllein, Jennifer, Jethwa, Alexander, Ellert, Elena, Walther, Tatjana, Liu, Xiyang, Dyer, Martin J.S., Elter, Thomas, Brummer, Tilman, Zeiser, Robert, Hermann, Michael, Herold, Michael, Weichert, Wilko, Dearden, Claire, Haferlach, Torsten, Seiffert, Martina, Hallek, Michael, von Kalle, Christof, Ho, Anthony D., Gaehler, Anita, Andrulis, Mindaugas, Steurer, Michael, and Zenz, Thorsten

Published
2016
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25. aRgus: multilevel visualization of non-synonymous single nucleotide variants & advanced pathogenicity score modeling for genetic vulnerability assessment

Author

Schröter, Julian, primary, Dattner, Tal, additional, Hüllein, Jennifer, additional, Jayme, Alejandra, additional, Heuveline, Vincent, additional, Hoffmann, Georg F., additional, Kölker, Stefan, additional, Lenz, Dominic, additional, Opladen, Thomas, additional, Popp, Bernt, additional, Schaaf, Christian P., additional, Staufner, Christian, additional, Syrbe, Steffen, additional, Uhrig, Sebastian, additional, Hübschmann, Daniel, additional, and Brennenstuhl, Heiko, additional

Published
2022
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26. Bcl‐x Las prognostic marker and potential therapeutic target in cholangiocarcinoma

Author

Hoffmeister‐Wittmann, Paula, primary, Mock, Andreas, additional, Nichetti, Federico, additional, Korell, Felix, additional, Heilig, Christoph E., additional, Scherr, Anna‐Lena, additional, Günther, Michael, additional, Albrecht, Thomas, additional, Kelmendi, Eblina, additional, Xu, Kaiyu, additional, Nader, Luisa, additional, Kessler, Annika, additional, Schmitt, Nathalie, additional, Fritzsche, Sarah, additional, Weiler, Sofia, additional, Sobol, Benjamin, additional, Stenzinger, Albrecht, additional, Boeck, Stefan, additional, Westphalen, Christoph B., additional, Schulze‐Osthoff, Klaus, additional, Trojan, Jörg, additional, Kindler, Thomas, additional, Weichert, Wilko, additional, Spiekermann, Karsten, additional, Bitzer, Michael, additional, Folprecht, Gunnar, additional, Illert, Anna L., additional, Boerries, Melanie, additional, Klauschen, Frederick, additional, Ochsenreither, Sebastian, additional, Siveke, Jens, additional, Bauer, Sebastian, additional, Glimm, Hanno, additional, Brors, Benedikt, additional, Hüllein, Jennifer, additional, Hübschmann, Daniel, additional, Uhrig, Sebastian, additional, Horak, Peter, additional, Kreutzfeldt, Simon, additional, Banales, Jesus M., additional, Springfeld, Christoph, additional, Jäger, Dirk, additional, Schirmacher, Peter, additional, Roessler, Stephanie, additional, Ormanns, Steffen, additional, Goeppert, Benjamin, additional, Fröhling, Stefan, additional, and Köhler, Bruno C., additional

Published
2022
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27. Drug-perturbation-based stratification of blood cancer

Author

Dietrich, Sascha, Oleś, Małgorzata, Lu, Junyan, Sellner, Leopold, Anders, Simon, Velten, Britta, Wu, Bian, Hüllein, Jennifer, da Silva Liberio, Michelle, Walther, Tatjana, Wagner, Lena, Rabe, Sophie, Ghidelli-Disse, Sonja, Bantscheff, Marcus, Oleś, Andrzej K., Słabicki, Mikołaj, 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, Dürig, Jan, Ringshausen, Ingo, Zapatka, Marc, Huber, Wolfgang, and Zenz, Thorsten

Published
2018
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29. MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers

Author

Niger, Monica, primary, Nichetti, Federico, additional, Casadei‐Gardini, Andrea, additional, Morano, Federica, additional, Pircher, Chiara, additional, Tamborini, Elena, additional, Perrone, Federica, additional, Canale, Matteo, additional, Lipka, Daniel B., additional, Vingiani, Andrea, additional, Agnelli, Luca, additional, Dobberkau, Anna, additional, Hüllein, Jennifer, additional, Korell, Felix, additional, Heilig, Christoph E., additional, Pusceddu, Sara, additional, Corti, Francesca, additional, Droz, Michele, additional, Ulivi, Paola, additional, Prisciandaro, Michele, additional, Antista, Maria, additional, Bini, Marta, additional, Cattaneo, Laura, additional, Milione, Massimo, additional, Glimm, Hanno, additional, Köhler, Bruno C., additional, Pruneri, Giancarlo, additional, Hübschmann, Daniel, additional, Fröhling, Stefan, additional, Mazzaferro, Vincenzo, additional, Pietrantonio, Filippo, additional, Di Bartolomeo, Maria, additional, and de Braud, Filippo, additional

Published
2022
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30. The protein landscape of chronic lymphocytic leukemia

Author

Meier-Abt, Fabienne, primary, Lu, Junyan, additional, Cannizzaro, Ester, additional, Pohly, Marcel F., additional, Kummer, Sandra, additional, Pfammatter, Sibylle, additional, Kunz, Laura, additional, Collins, Ben C., additional, Nadeu, Ferran, additional, Lee, Kwang Seok, additional, Xue, Peng, additional, Gwerder, Myriam, additional, Roiss, Michael, additional, Hüllein, Jennifer, additional, Scheinost, Sebastian, additional, Dietrich, Sascha, additional, Campo, Elias, additional, Huber, Wolfgang, additional, Aebersold, Ruedi, additional, and Zenz, Thorsten, additional

Published
2021
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31. Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Author

Horak, Peter, primary, Heining, Christoph, additional, Kreutzfeldt, Simon, additional, Hutter, Barbara, additional, Mock, Andreas, additional, Hüllein, Jennifer, additional, Fröhlich, Martina, additional, Uhrig, Sebastian, additional, Jahn, Arne, additional, Rump, Andreas, additional, Gieldon, Laura, additional, Möhrmann, Lino, additional, Hanf, Dorothea, additional, Teleanu, Veronica, additional, Heilig, Christoph E., additional, Lipka, Daniel B., additional, Allgäuer, Michael, additional, Ruhnke, Leo, additional, Laßmann, Andreas, additional, Endris, Volker, additional, Neumann, Olaf, additional, Penzel, Roland, additional, Beck, Katja, additional, Richter, Daniela, additional, Winter, Ulrike, additional, Wolf, Stephan, additional, Pfütze, Katrin, additional, Geörg, Christina, additional, Meißburger, Bettina, additional, Buchhalter, Ivo, additional, Augustin, Marinela, additional, Aulitzky, Walter E., additional, Hohenberger, Peter, additional, Kroiss, Matthias, additional, Schirmacher, Peter, additional, Schlenk, Richard F., additional, Keilholz, Ulrich, additional, Klauschen, Frederick, additional, Folprecht, Gunnar, additional, Bauer, Sebastian, additional, Siveke, Jens Thomas, additional, Brandts, Christian H., additional, Kindler, Thomas, additional, Boerries, Melanie, additional, Illert, Anna L., additional, von Bubnoff, Nikolas, additional, Jost, Philipp J., additional, Spiekermann, Karsten, additional, Bitzer, Michael, additional, Schulze-Osthoff, Klaus, additional, von Kalle, Christof, additional, Klink, Barbara, additional, Brors, Benedikt, additional, Stenzinger, Albrecht, additional, Schröck, Evelin, additional, Hübschmann, Daniel, additional, Weichert, Wilko, additional, Glimm, Hanno, additional, and Fröhling, Stefan, additional

Published
2021
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33. Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia

Author

Jethwa, Alexander, Hüllein, Jennifer, Stolz, Tatjana, Blume, Carolin, Sellner, Leopold, Jauch, Anna, Sill, Martin, Kater, Arnon P., te Raa, Doreen G., Geisler, Christian, van Oers, Marinus, Dietrich, Sascha, Dreger, Peter, Ho, Anthony D., Paruzynski, Anna, Schmidt, Manfred, von Kalle, Christof, Glimm, Hanno, and Zenz, Thorsten

Published
2013
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34. MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma

Author

Hüllein, Jennifer, Słabicki, Mikołaj, Rosolowski, Maciej, Jethwa, Alexander, Habringer, Stefan, Tomska, Katarzyna, Kurilov, Roma, Lu, Junyan, Scheinost, Sebastian, Wagener, Rabea, Huang, Zhiqin, Lukas, Marina, Yavorska, Olena, Helfrich, Hanne, Scholtysik, René, Bonneau, Kyle, Tedesco, Donato, Küppers, Ralf, Klapper, Wolfram, Pott, Christiane, Stilgenbauer, Stephan, Burkhardt, Birgit, Löffler, Markus, Trümper, Lorenz H, Hummel, Michael, Brors, Benedikt, Zapatka, Marc, Siebert, Reiner, Kreuz, Markus, Keller, Ulrich, et al, and University of Zurich

Subjects
10032 Clinic for Oncology and Hematology, 610 Medicine & health, 2730 Oncology, 1306 Cancer Research
Published
2019

35. Abstract 3437: Requirement for YAP1 signaling in myxoid liposarcoma

Author

Trautmann, Marcel, primary, Cheng, Ya-Yun, additional, Jensen, Patrizia, additional, Azoitei, Ninel, additional, Brunner, Ines, additional, Hüllein, Jennifer, additional, Slabicki, Mikolaj, additional, Isfort, Ilka, additional, Cyra, Magdalene, additional, Wardelmann, Eva, additional, Huss, Sebastian, additional, Altvater, Bianca, additional, Rossig, Claudia, additional, Hafner, Susanne, additional, Simmet, Thomas, additional, Ståhlberg, Anders, additional, Åman, Pierre, additional, Zenz, Thorsten, additional, Lange, Undine, additional, Kindler, Thomas, additional, Scholl, Claudia, additional, Hartmann, Wolfgang, additional, and Fröhling, Stefan, additional

Published
2019
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36. MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma

Author

Hüllein, Jennifer, primary, Słabicki, Mikołaj, additional, Rosolowski, Maciej, additional, Jethwa, Alexander, additional, Habringer, Stefan, additional, Tomska, Katarzyna, additional, Kurilov, Roma, additional, Lu, Junyan, additional, Scheinost, Sebastian, additional, Wagener, Rabea, additional, Huang, Zhiqin, additional, Lukas, Marina, additional, Yavorska, Olena, additional, Helfrich, Hanne, additional, Scholtysik, René, additional, Bonneau, Kyle, additional, Tedesco, Donato, additional, Küppers, Ralf, additional, Klapper, Wolfram, additional, Pott, Christiane, additional, Stilgenbauer, Stephan, additional, Burkhardt, Birgit, additional, Löffler, Markus, additional, Trümper, Lorenz H., additional, Hummel, Michael, additional, Brors, Benedikt, additional, Zapatka, Marc, additional, Siebert, Reiner, additional, Kreuz, Markus, additional, Keller, Ulrich, additional, Huber, Wolfgang, additional, and Zenz, Thorsten, additional

Published
2019
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37. Requirement for YAP1 signaling in myxoid liposarcoma

Author

Trautmann, Marcel, primary, Cheng, Ya‐Yun, additional, Jensen, Patrizia, additional, Azoitei, Ninel, additional, Brunner, Ines, additional, Hüllein, Jennifer, additional, Slabicki, Mikolaj, additional, Isfort, Ilka, additional, Cyra, Magdalene, additional, Berthold, Ruth, additional, Wardelmann, Eva, additional, Huss, Sebastian, additional, Altvater, Bianca, additional, Rossig, Claudia, additional, Hafner, Susanne, additional, Simmet, Thomas, additional, Ståhlberg, Anders, additional, Åman, Pierre, additional, Zenz, Thorsten, additional, Lange, Undine, additional, Kindler, Thomas, additional, Scholl, Claudia, additional, Hartmann, Wolfgang, additional, and Fröhling, Stefan, additional

Published
2019
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38. The Influence of the Bone Marrow Niche on Drug Response Phenotypes of Blood Cancers

Author

Rabe, Sophie, primary, Schitter, Eva, additional, Roider, Tobias, additional, Bruch, Peter-Martin, additional, Kolb, Carolin, additional, Stolarczyk, Marta, additional, Hüllein, Jennifer, additional, Lu, Junyan, additional, von Kalle, Christof, additional, Lutz, Christoph, additional, Dreger, Peter, additional, Mueller-Tidow, Carsten, additional, Zenz, Thorsten, additional, Huber, Wolfgang, additional, and Dietrich, Sascha, additional

Published
2018
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39. Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

Author

Durham, Benjamin H., Getta, Bartlomiej, Dietrich, Sascha, Taylor, Justin, Won, Helen, Bogenberger, James M., Scott, Sasinya, Kim, Eunhee, Chung, Young Rock, Chung, Stephen S., Hüllein, Jennifer, Walther, Tatjana, Wang, Lu, Lu, Sydney X., Oakes, Christopher C., Tibes, Raoul, Haferlach, Torsten, Taylor, Barry S., Tallman, Martin S., Berger, Michael F., Park, Jae H., Zenz, Thorsten, and Abdel-Wahab, Omar

Published
2017
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40. Identification of Burkitt lymphoma vulnerabilities using RNAi

Author

Hüllein, Jennifer

Subjects
500 Natural sciences and mathematics, 570 Life sciences
Abstract

Oncogenic activation of MYC drives cell proliferation in Burkitt lymphoma (BL), but also evokes stress signals that have to be counterbalanced to escape apoptosis. Pro-survival signals from tonic B cell receptor and PI3K signaling are essential, but additional mutations are required for malignant transformation. TP53 mutations were identified in 43% of BL patients. Mutations in the conserved MYC box I that abrogate activation of pro-apoptotic Bcl2-family member Bim were present in 17% of BL patients. Notably, MYC box I and TP53 mutations occurred independently and accounted for 54% of cases, suggesting that alternative failsafe mechanisms may be inactivated in BL. To study alternative mechanisms of transformation in the absence of TP53 mutations, we analyzed the pattern of recurrent genetic aberrations in BL for associations with TP53 status. We observed an overrepresentation of chromosome 1q gains in TP53 wild-type BL patients, which was not observed in diffuse large B cell lymphoma (DLBCL) patients. Minimally gained regions comprised 1q21-q23 and 1q32 and amplified regions displayed a gene dosage effect as shown by gene expression analysis. To identify genes essential for p53 wild-type BL cells we performed a RNAi loss-of-function screen in a panel of genetically defined cell lines. We used a pooled shRNA library targeting 5,000 genes in key signaling pathways across the genome. Our data was probed against published RNAi screens across cancer entities and showed a high overlap of common essential and non-essential genes. p53 wild-type BL cell lines showed a strong and specific dependence on the p53 inhibitor MDM4. Depletion of MDM4 resulted in an upregulation of p53 target genes and induced cell cycle arrest. In a mouse xenograft model, MDM4 knock-down significantly reduced tumor growth. These effects were p53 dependent as confirmed in an isogenic p53 knock-out cell line. MDM4 is located within the minimally gained region 1q32 associated with p53 wild-type BL patients and might therefore contribute to BL pathogenesis by inactivation of the p53 pathway. Our data suggest that reactivation of p53 in patients lacking TP53 mutation, e.g. by specific MDM4 inhibition, is a promising therapeutic approach. Re-analysis of published RNAi screening data revealed p53-specific sensitivity of MDM4 knock-down across cancer cell lines, suggesting a broader application for MDM4 inhibitors. Our data set on essential genes in Burkitt lymphoma proved to be a valuable resource for identification of genotype-specific vulnerabilities. This analysis could be extended by integration of published RNAi screening data in non-lymphoid cell lines to identify interesting potential entity-specific vulnerabilities.

Published
2017

41. Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia

Author

Leeksma, Alexander C., primary, Taylor, Justin, additional, Wu, Bian, additional, Gardner, Jeffrey R., additional, He, Jie, additional, Nahas, Michelle, additional, Gonen, Mithat, additional, Alemayehu, Wendimagegn G., additional, te Raa, Doreen, additional, Walther, Tatjana, additional, Hüllein, Jennifer, additional, Dietrich, Sascha, additional, Claus, Rainer, additional, de Boer, Fransien, additional, de Heer, Koen, additional, Dubois, Julie, additional, Dampmann, Maria, additional, Dürig, Jan, additional, van Oers, Marinus H. J., additional, Geisler, Christian H., additional, Eldering, Eric, additional, Levine, Ross L., additional, Miller, Vincent, additional, Mughal, Tariq, additional, Lamanna, Nicole, additional, Frattini, Mark G., additional, Heaney, Mark L., additional, Zelenetz, Andrew, additional, Zenz, Thorsten, additional, Abdel-Wahab, Omar, additional, and Kater, Arnon P., additional

Published
2018
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42. 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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43. Drug-perturbation-based stratification of blood cancer

Author

Daum, Steffen, Šíša, Miroslav, Dietrich, Sascha, Oleś, Małgorzata, Lu, Junyan, Sellner, Leopold, Anders, Simon, Velten, Britta, Wu, Bian, Hüllein, Jennifer, Silva Liberio, Michelle da, Walther, Tatjana, Wagner, Lena, Rabe, Sophie, Ghidelli-Disse, Sonja, Bantscheff, Marcus, Oleś, Andrzej K., Słabicki, Mikołaj, 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, Kalle, Christof von, Ho, Anthony Dick, Hensel, Manfred, Dürig, Jan, Ringshausen, Ingo, Zapatka, Marc, Huber, Wolfgang, Zenz, Thorsten, Daum, Steffen, Šíša, Miroslav, Dietrich, Sascha, Oleś, Małgorzata, Lu, Junyan, Sellner, Leopold, Anders, Simon, Velten, Britta, Wu, Bian, Hüllein, Jennifer, Silva Liberio, Michelle da, Walther, Tatjana, Wagner, Lena, Rabe, Sophie, Ghidelli-Disse, Sonja, Bantscheff, Marcus, Oleś, Andrzej K., Słabicki, Mikołaj, 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, Kalle, Christof von, Ho, Anthony Dick, Hensel, Manfred, Dürig, Jan, Ringshausen, Ingo, Zapatka, Marc, Huber, Wolfgang, and Zenz, Thorsten

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.

Published
2017

44. Recurrent CDKN1B (p27) mutations in hairy cell leukemia

Author

Dietrich, Sascha, Hüllein, Jennifer, Lee, Stanley Chun-Wei, Hutter, Barbara, Gonzalez, David, Jayne, Sandrine, Dyer, Martin J.S., Oleś, Małgorzata, Else, Monica, Liu, Xiyang, Słabicki, Mikołaj, Wu, Bian, Troussard, Xavier, Dürig, Jan, Andrulis, Mindaugas, Dearden, Claire, von Kalle, Christof, Granzow, Martin, Jauch, Anna, Fröhling, Stefan, Huber, Wolfgang, Meggendorfer, Manja, Haferlach, Torsten, Ho, Anthony D., Richter, Daniela, Brors, Benedikt, Glimm, Hanno, Matutes, Estella, Abdel Wahab, Omar, and Zenz, Thorsten

Published
2015
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45. Systematic mapping of drug sensitivity in hematological malignancies identifies vulnerability of chronic lymphocytic leukemia with mutant p53

Author

Sellner, Leopold, Dietrich, Sascha, Lukas, Marina, Ho, Anthony D., Blume, Carolin, Stolz, Tatjana, Hensel, Manfred, Rossi, Davide, Zenz, Thorsten, Zirlik, Katja, Glimm, Hanno, Oles, Malgorzata, Huber, Wolfgang, Seiffert, Martina, Slabicki, Mikolaj, Sill, Martin, Kalle, Christof von, Jauch, Anna, Hüllein, Jennifer, Ringshausen, Ingo, Merkel, Olaf, Dreger, Peter, Herling, Marco, Dürig, Jan, and Oakes, Christopher C.

Subjects
Medizin
Published
2014

46. Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia

Author

Leeksma, Alexander, Taylor, Justin, Wu, Bian, Gardner, Jeffrey, He, Jie, Nahas, Michelle, Gonen, Mithat, Alemayehu, Wendimagegn, Raa, Doreen, Walther, Tatjana, Hüllein, Jennifer, Dietrich, Sascha, Claus, Rainer, de Boer, Fransien, de Heer, Koen, Dubois, Julie, Dampmann, Maria, Dürig, Jan, van Oers, Marinus, Geisler, Christian, Eldering, Eric, Levine, Ross, Miller, Vincent, Mughal, Tariq, Lamanna, Nicole, Frattini, Mark, Heaney, Mark, Zelenetz, Andrew, Zenz, Thorsten, Abdel-Wahab, Omar, and Kater, Arnon

Abstract

Genomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driver genes using targeted next-generation sequencing in 643 CLL patients and found higher frequencies of mutations in TP53(35 vs. 12%, p< 0.001) and SF3B1(20 vs. 11%, p< 0.05) and increased number of (sub)clonal (p< 0.0001) mutations in treated patients. We next performed an in-depth evaluation of clonal evolution on untreated CLL patients (50 “progressors” and 17 matched “non-progressors”) using a 404 gene-sequencing panel and identified novel mutated genes such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried more mutations at initial presentation (2.5 vs. 1, p< 0.0001). Mutations in specific genes were associated with increased (SF3B1, ATM, and FBXW7) or decreased progression risk (AXIN1and MYD88). Mutations affecting specific signaling pathways, such as Notch and MAP kinase pathway were enriched in progressive relative to non-progressive patients. These data extend earlier findings that specific genomic alterations and diversity of subclones are associated with disease progression and persistence of disease in CLL and identify novel recurrently mutated genes and associated outcomes.

Published
2019
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47. Abstract 5557: Systematic mapping of drug sensitivity in hematological malignancies identifies vulnerability of chronic lymphocytic leukemia with mutant p53

Author

Sellner, Leopold, primary, Oles, Malgorzata, additional, Slabicki, Mikolaj, additional, Blume, Carolin, additional, Hüllein, Jennifer, additional, Stolz, Tatjana, additional, Lukas, Marina, additional, Sill, Martin, additional, Oakes, Christopher C., additional, Dietrich, Sascha, additional, Merkel, Olaf, additional, Jauch, Anna, additional, Hensel, Manfred, additional, Rossi, Davide, additional, Zirlik, Katja, additional, Dürig, Jan, additional, Ringshausen, Ingo, additional, Herling, Marco, additional, Seiffert, Martina, additional, Dreger, Peter, additional, Kalle, Christof von, additional, Ho, Anthony D., additional, Glimm, Hanno, additional, Huber, Wolfgang, additional, and Zenz, Thorsten, additional

Published
2014
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48. Heterogeneity and Evolution Of DNA Methylation In Chronic Lymphocytic Leukemia

Author

Oakes, Christopher C, primary, Claus, Rainer, additional, Gu, Lei, additional, Assenov, Yassen, additional, Hüllein, Jennifer, additional, Zucknick, Manuela, additional, Brocks, David, additional, Bogatyrova, Olga, additional, Schmidt, Christopher R., additional, Rassenti, Laura, additional, Kipps, Thomas J., additional, Mertens, Daniel, additional, Lichter, Peter, additional, Döhner, Hartmut, additional, Stilgenbauer, Stephan, additional, Byrd, John C., additional, Zenz, Thorsten, additional, and Plass, Christoph, additional

Published
2013
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49. Systematic Mapping Of Drug and Pathway Sensitivity In Chronic Lymphocytic Leukemia Identifies Synthetic Lethal Interactions Of Mutant p53

Author

Wolfgang Huber, Carolin Blume, Hüllein Jennifer, Hanno Glimm, Martina Seiffert, Mikolaj Slabicki, Sascha Dietrich, Oles Malgorzata, Anthony D. Ho, Davide Rossi, Olaf Merkel, Tatjana Stolz, Manfred Hensel, Martin Sill, Anna Jauch, von Kalle Christof, Thorsten Zenz, Leopold Sellner, and Zirlik Katja

Subjects
biology, Chronic lymphocytic leukemia, Immunology, breakpoint cluster region, Cell Biology, Hematology, medicine.disease, Biochemistry, Fludarabine, Dasatinib, chemistry.chemical_compound, chemistry, hemic and lymphatic diseases, Ibrutinib, biology.protein, medicine, Cancer research, Bruton's tyrosine kinase, Viability assay, PI3K/AKT/mTOR pathway, medicine.drug
Abstract

Introduction Critical pathway alterations contribute to heterogeneous biology and clinical course in chronic lymphocytic leukemia (CLL). The role of particular mutations for drug sensitivity has been demonstrated for CLL and other entities. Here we systematically investigated heterogeneity of drug response and genetic lesions in primary CLL. The comprehensive identification of pathway dependencies will lead to a better understanding of hematologic malignancies and this may be exploited by development of rational-driven treatment approaches. Methods Primary CLL cells were characterized through an ex vivo high-throughput drug screening platform in 384-well format. The drug library consisted of 67 compounds (inhibitors targeting critical pathways in CLL and other cancers as well as compounds with known activity against CLL cells (including ABT-263, CAL-101, dasatinib, fludarabine, ibrutinib)) at different concentrations. Heat inactivated human serum was supplemented to mimic micro-environmental conditions. CLL samples represented untreated CLL, sensitive or refractory disease as well as major genetic subgroups. Cell viability was assessed by quantification of ATP (CellTiterGlo®) 48 and 72 hours after drug application. To understand heterogeneous pathway dependencies, drug sensitivity was regressed on genetic profiles. Genetic characterization was performed by FISH, targeted sequencing of recurrent aberrations (BRAF, MYD88, NOTCH1, SF3B1, TP53) as well as whole exome sequencing. Results We report results from 97 primary CLL samples screened ex vivo. Validity of the approach was demonstrated by the response profiles of p53-interfering compounds: Nutlin-3a and fludarabine induced cell death in cells with wild-type (n=80) but considerably lessin CLL with mutated p53(n=17; Nutlin-3a 10µM: 51±18vs80±18;fludarabine 10µM: 40±36vs 67±23 [% viability of untreated control], both p Conclusion Our data provide a first comprehensive map of genetically determined drug sensitivity in CLL. The work offers a novel functional classification of CLL based on drug sensitivity and identifies synthetic lethal interaction for TP53 mutant CLL. Disclosures: No relevant conflicts of interest to declare.

Published
2013

50. Continued Response Off Treatment After BRAF Inhibition in Refractory Hairy Cell Leukemia

Author

Dietrich, Sascha, primary, Hüllein, Jennifer, additional, Hundemer, Michael, additional, Lehners, Nicola, additional, Jethwa, Alexander, additional, Capper, David, additional, Acker, Till, additional, Garvalov, Boyan K., additional, Andrulis, Mindaugas, additional, Blume, Carolin, additional, Schulte, Christoph, additional, Mandel, Thomas, additional, Meissner, Julia, additional, Fröhling, Stefan, additional, von Kalle, Christof, additional, Glimm, Hanno, additional, Ho, Anthony D., additional, and Zenz, Thorsten, additional

Published
2013
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