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160 results on '"Lübbert, A."'

1. The new WHO 2022 and ICC proposals for the classification of myelodysplastic neoplasms. Validation based on the Düsseldorf MDS Registry and proposals for a merged classification

Author

Nachtkamp, K., Strupp, C., Vukelja, M., Kasprzak, A., Haase, D., Ganster, C., Hildebrandt, B., Betz, B., Giagounidis, A., Aul, C., Blum, S., Hofmann, W. K., Pfeilstöcker, M., Valent, P., Lübbert, M., Seidl, M., Rudelius, M., Stauder, R., Krieger, O., Götze, K. S., Bobak, J., Kündgen, A., Schulz, F., Dietrich, S., Kobbe, G., Gattermann, N., and Germing, U.

Published
2024
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2. In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts

Author

Greve, Gabriele, Andrieux, Geoffroy, Schlosser, Pascal, Blagitko-Dorfs, Nadja, Rehman, Usama-Ur, Ma, Tobias, Pfeifer, Dietmar, Heil, Gerhard, Neubauer, Andreas, Krauter, Jürgen, Heuser, Michael, Salih, Helmut R., Döhner, Konstanze, Döhner, Hartmut, Hackanson, Björn, Boerries, Melanie, and Lübbert, Michael

Published
2023
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4. Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification—an approach to classification of patients with t-MDS

Author

Kuendgen, A., Nomdedeu, M., Tuechler, H., Garcia-Manero, G., Komrokji, R. S., Sekeres, M. A., Della Porta, M. G., Cazzola, M., DeZern, A. E., Roboz, G. J., Steensma, D. P., Van de Loosdrecht, A. A., Schlenk, R. F., Grau, J., Calvo, X., Blum, S., Pereira, A., Valent, P., Costa, D., Giagounidis, A., Xicoy, B., Döhner, H., Platzbecker, U., Pedro, C., Lübbert, M., Oiartzabal, I., Díez-Campelo, M., Cedena, M. T., Machherndl-Spandl, S., López-Pavía, M., Baldus, C. D., Martinez-de-Sola, M., Stauder, R., Merchan, B., List, A., Ganster, C., Schroeder, T., Voso, M. T., Pfeilstöcker, M., Sill, H., Hildebrandt, B., Esteve, J., Nomdedeu, B., Cobo, F., Haas, R., Sole, F., Germing, U., Greenberg, P. L., Haase, D., and Sanz, G.

Published
2021
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5. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia

Author

Madan, V, Shyamsunder, P, Han, L, Mayakonda, A, Nagata, Y, Sundaresan, J, Kanojia, D, Yoshida, K, Ganesan, S, Hattori, N, Fulton, N, Tan, K-T, Alpermann, T, Kuo, M-C, Rostami, S, Matthews, J, Sanada, M, Liu, L-Z, Shiraishi, Y, Miyano, S, Chendamarai, E, Hou, H-A, Malnassy, G, Ma, T, Garg, M, Ding, L-W, Sun, Q-Y, Chien, W, Ikezoe, T, Lill, M, Biondi, A, Larson, RA, Powell, BL, Lübbert, M, Chng, WJ, Tien, H-F, Heuser, M, Ganser, A, Koren-Michowitz, M, Kornblau, SM, Kantarjian, HM, Nowak, D, Hofmann, W-K, Yang, H, Stock, W, Ghavamzadeh, A, Alimoghaddam, K, Haferlach, T, Ogawa, S, Shih, L-Y, Mathews, V, and Koeffler, HP

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Human Genome, Childhood Leukemia, Pediatric Cancer, Genetics, Rare Diseases, Hematology, Clinical Research, Pediatric, Cell Differentiation, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Gene Expression Profiling, Humans, Leukemia, Promyelocytic, Acute, Nuclear Proteins, Recurrence, Transcription Factors, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Abstract

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Published
2016

6. Functional and clinical characterization of the alternatively spliced isoform AML1-ETO9a in adult patients with translocation t(8;21)(q22;q22.1) acute myeloid leukemia (AML)

Author

Agrawal, Mridul, Schwarz, Peggy, Giaimo, Benedetto Daniele, Bedzhov, Ivan, Corbacioglu, Andrea, Weber, Daniela, Gaidzik, Verena I., Jahn, Nikolaus, Rücker, Frank G., Schroeder, Thomas, Kindler, Thomas, Wattad, Mohammed, Götze, Katharina, Lübbert, Michael, Salwender, Hans, Ringhoffer, Mark, Lange, Elisabeth, Koller, Elisabeth, Thol, Felicitas, Heuser, Michael, Ganser, Arnold, Bullinger, Lars, Paschka, Peter, Döhner, Hartmut, Geiger, Hartmut, Borggrefe, Tilman, Döhner, Konstanze, and Oswald, Franz

Published
2020
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7. In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts

Author

Gabriele Greve, Geoffroy Andrieux, Pascal Schlosser, Nadja Blagitko-Dorfs, Usama-Ur Rehman, Tobias Ma, Dietmar Pfeifer, Gerhard Heil, Andreas Neubauer, Jürgen Krauter, Michael Heuser, Helmut R. Salih, Konstanze Döhner, Hartmut Döhner, Björn Hackanson, Melanie Boerries, and Michael Lübbert

Subjects
Cancer Research, Oncology, ddc:610, Hematology
Abstract

Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m2 day 1–5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analyses (days 0 and 8; n = 16). We noted massive, non-random demethylation at day 8, which was variable between patients. In contrast, T-cells disclosed a thousand-fold lesser, random demethylation, indicating selectivity of the demethylation for the malignant blasts. The integrative analysis of DNA demethylation and transcript induction revealed 87 genes displaying a significant inverse correlation, e.g. the tumor suppressor gene IFI27, whose derepression was validated in two AML cell lines. These results support HMA-induced, non-random early in vivo demethylation events in AML blasts associated with gene induction. Larger patient cohorts are needed to determine whether a demethylation signature may be predictive for response to this treatment.

Published
2023
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8. LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML

Author

Barth, Jessica, Abou-El-Ardat, Khalil, Dalic, Denis, Kurrle, Nina, Maier, Anna-Maria, Mohr, Sebastian, Schütte, Judith, Vassen, Lothar, Greve, Gabriele, Schulz-Fincke, Johannes, Schmitt, Martin, Tosic, Milica, Metzger, Eric, Bug, Gesine, Khandanpour, Cyrus, Wagner, Sebastian A., Lübbert, Michael, Jung, Manfred, Serve, Hubert, Schüle, Roland, and Berg, Tobias

Published
2019
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10. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia—results of the AMLSG 11-08 trial

Author

Paschka, Peter, Schlenk, Richard F, Weber, Daniela, Benner, Axel, Bullinger, Lars, Heuser, Michael, Gaidzik, Verena I, Thol, Felicitas, Agrawal, Mridul, Teleanu, Veronica, Lübbert, Michael, Fiedler, Walter, Radsak, Markus, Krauter, Jürgen, Horst, Heinz-A., Greil, Richard, Mayer, Karin, Kündgen, Andrea, Martens, Uwe, Heil, Gerhard, Salih, Helmut R, Hertenstein, Bernd, Schwänen, Carsten, Wulf, Gerald, Lange, Elisabeth, Pfreundschuh, Michael, Ringhoffer, Mark, Girschikofsky, Michael, Heinicke, Thomas, Kraemer, Doris, Göhring, Gudrun, Ganser, Arnold, Döhner, Konstanze, and Döhner, Hartmut

Published
2018
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12. Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis

Author

Thol, F, Klesse, S, Köhler, L, Gabdoulline, R, Kloos, A, Liebich, A, Wichmann, M, Chaturvedi, A, Fabisch, J, Gaidzik, V I, Paschka, P, Bullinger, L, Bug, G, Serve, H, Göhring, G, Schlegelberger, B, Lübbert, M, Kirchner, H, Wattad, M, Kraemer, D, Hertenstein, B, Heil, G, Fiedler, W, Krauter, J, Schlenk, R F, Döhner, K, Döhner, H, Ganser, A, and Heuser, M

Published
2017
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15. Prevalence, clonal dynamics and clinical impact of TP53 mutations in patients with myelodysplastic syndrome with isolated deletion (5q) treated with lenalidomide: results from a prospective multicenter study of the german MDS study group (GMDS)

Author

Mossner, M, Jann, J-C, Nowak, D, Platzbecker, U, Giagounidis, A, Götze, K, Letsch, A, Haase, D, Shirneshan, K, Braulke, F, Schlenk, R F, Haferlach, T, Schafhausen, P, Bug, G, Lübbert, M, Ganser, A, Büsche, G, Schuler, E, Nowak, V, Pressler, J, Obländer, J, Fey, S, Müller, N, Lauinger-Lörsch, E, Metzgeroth, G, Weiß, C, Hofmann, W-K, Germing, U, and Nolte, F

Published
2016
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16. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

Author

Julia Stomper, John Charles Rotondo, Michael Lübbert, and Gabriele Greve

Subjects
Myeloid, Cancer Research, Azacitidine, Drug Resistance, Decitabine, Drug resistance, Review Article, Acute, Acute myeloid leukaemia, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, DNA Methylation, Drug Resistance, Neoplasm, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Treatment Outcome, Leukemia, business.industry, Myelodysplastic syndromes, Myeloid leukemia, Ambientale, Hematology, medicine.disease, Cancer therapeutic resistance, medicine.anatomical_structure, Oncology, DNA methylation, Cancer research, Neoplasm, business, Myelodysplastic syndrome, medicine.drug
Abstract

Aberrant DNA methylation plays a pivotal role in tumor development and progression. DNA hypomethylating agents (HMA) constitute a class of drugs which are able to reverse DNA methylation, thereby triggering the re-programming of tumor cells. The first-generation HMA azacitidine and decitabine have now been in standard clinical use for some time, offering a valuable alternative to previous treatments in acute myeloid leukemia and myelodysplastic syndromes, so far particularly in older, medically non-fit patients. However, the longer we use these drugs, the more we are confronted with the (almost inevitable) development of resistance. This review provides insights into the mode of action of HMA, mechanisms of resistance to this treatment, and strategies to overcome HMA resistance including next-generation HMA and HMA-based combination therapies.

Published
2021

17. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey

Author

Zeiser, R, Burchert, A, Lengerke, C, Verbeek, M, Maas-Bauer, K, Metzelder, S K, Spoerl, S, Ditschkowski, M, Ecsedi, M, Sockel, K, Ayuk, F, Ajib, S, de Fontbrune, F S, Na, I-K, Penter, L, Holtick, U, Wolf, D, Schuler, E, Meyer, E, Apostolova, P, Bertz, H, Marks, R, Lübbert, M, Wäsch, R, Scheid, C, Stölzel, F, Ordemann, R, Bug, G, Kobbe, G, Negrin, R, Brune, M, Spyridonidis, A, Schmitt-Gräff, A, van der Velden, W, Huls, G, Mielke, S, Grigoleit, G U, Kuball, J, Flynn, R, Ihorst, G, Du, J, Blazar, B R, Arnold, R, Kröger, N, Passweg, J, Halter, J, Socié, G, Beelen, D, Peschel, C, Neubauer, A, Finke, J, Duyster, J, and von Bubnoff, N

Published
2015
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18. Correction: LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML

Author

Barth, Jessica, Abou-El-Ardat, Khalil, Dalic, Denis, Kurrle, Nina, Maier, Anna-Maria, Mohr, Sebastian, Schütte, Judith, Vassen, Lothar, Greve, Gabriele, Schulz-Fincke, Johannes, Schmitt, Martin, Tosic, Milica, Metzger, Eric, Bug, Gesine, Khandanpour, Cyrus, Wagner, Sebastian A., Lübbert, Michael, Jung, Manfred, Serve, Hubert, Schüle, Roland, and Berg, Tobias

Published
2019
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19. Clinical impact of GATA2 mutations in acute myeloid leukemia patients harboring CEBPA mutations: a study of the AML study group

Author

Theis, F, Corbacioglu, A, Gaidzik, V I, Paschka, P, Weber, D, Bullinger, L, Heuser, M, Ganser, A, Thol, F, Schlegelberger, B, Göhring, G, Köhne, C-H, Germing, U, Brossart, P, Horst, H-A, Haase, D, Götze, K, Ringhoffer, M, Fiedler, W, Nachbaur, D, Kindler, T, Held, G, Lübbert, M, Wattad, M, Salih, H R, Krauter, J, Döhner, H, Schlenk, R F, and Döhner, K

Published
2016
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21. Monosomal karyotype in MDS: explaining the poor prognosis?

Author

Schanz, J, Tüchler, H, Solé, F, Mallo, M, Luño, E, Cervera, J, Grau, J, Hildebrandt, B, Slovak, M L, Ohyashiki, K, Steidl, C, Fonatsch, C, Pfeilstöcker, M, Nösslinger, T, Valent, P, Giagounidis, A, Aul, C, Lübbert, M, Stauder, R, Krieger, O, Le Beau, M M, Bennett, J M, Greenberg, P, Germing, U, and Haase, D

Published
2013
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23. Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study

Author

Germing, U, Lauseker, M, Hildebrandt, B, Symeonidis, A, Cermak, J, Fenaux, P, Kelaidi, C, Pfeilstöcker, M, Nösslinger, T, Sekeres, M, Maciejewski, J, Haase, D, Schanz, J, Seymour, J, Kenealy, M, Weide, R, Lübbert, M, Platzbecker, U, Valent, P, Götze, K, Stauder, R, Blum, S, Kreuzer, K-A, Schlenk, R, Ganser, A, Hofmann, W-K, Aul, C, Krieger, O, Kündgen, A, Haas, R, Hasford, J, and Giagounidis, A

Published
2012
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25. Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q

Author

Mallo, M, Cervera, J, Schanz, J, Such, E, García-Manero, G, Luño, E, Steidl, C, Espinet, B, Vallespí, T, Germing, U, Blum, S, Ohyashiki, K, Grau, J, Pfeilstöcker, M, Hernández, J M, Noesslinger, T, Giagounidis, A, Aul, C, Calasanz, M J, Martín, M L, Valent, P, Collado, R, Haferlach, C, Fonatsch, C, Lübbert, M, Stauder, R, Hildebrandt, B, Krieger, O, Pedro, C, Arenillas, L, Sanz, M Á, Valencia, A, Florensa, L, Sanz, G F, Haase, D, and Solé, F

Published
2011
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30. Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation

Author

Annika Baude, Ruth Meier, Dietmar Pfeifer, Pascal Schlosser, Gabriele Greve, Michael Lübbert, David Brocks, Christoph Plass, and Nadja Blagitko-Dorfs

Subjects
0301 basic medicine, Cancer Research, Down-Regulation, DNA Methyltransferase Inhibitor, Biology, Decitabine, Epigenesis, Genetic, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Panobinostat, Biomarkers, Tumor, Humans, Epigenetics, Enzyme Inhibitors, DNA Modification Methylases, SUV39H1, Regulation of gene expression, Valproic Acid, Drug Synergism, Hematology, DNA Methylation, Demethylation, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Leukemia, Myeloid, Acute, 030104 developmental biology, DNA demethylation, Oncology, chemistry, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, Histone deacetylase
Abstract

DNA methyltransferase inhibitors (DNMTi) approved for older AML patients are clinically tested in combination with histone deacetylase inhibitors (HDACi). The mechanism of action of these drugs is still under debate. In colon cancer cells, 5-aza-2'-deoxycytidine (DAC) can downregulate oncogenes and metabolic genes by reversing gene body DNA methylation, thus implicating gene body methylation as a novel drug target. We asked whether DAC-induced gene body demethylation in AML cells is also associated with gene repression, and whether the latter is enhanced by HDACi.Transcriptome analyses revealed that a combined treatment with DAC and the HDACi panobinostat or valproic acid affected significantly more transcripts than the sum of the genes regulated by either treatment alone, demonstrating a quantitative synergistic effect on genome-wide expression in U937 cells. This effect was particularly striking for downregulated genes. Integrative methylome and transcriptome analyses showed that a massive downregulation of genes, including oncogenes (e.g., MYC) and epigenetic modifiers (e.g., KDM2B, SUV39H1) often overexpressed in cancer, was associated predominantly with gene body DNA demethylation and changes in acH3K9/27. These findings have implications for the mechanism of action of combined epigenetic treatments, and for a better understanding of responses in trials where this approach is clinically tested.

Published
2018
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36. Quality assurance in RT-PCR-based BCR/ABL diagnostics – results of an interlaboratory test and a standardization approach

Author

Burmeister, T, Maurer, J, Aivado, M, Elmaagacli, AH, Grünebach, F, Held, KR, Heß, G, Hochhaus, A, Höppner, W, Lentes, KU, Lübbert, M, Schäfer, KL, Schafhausen, P, Schmidt, CA, Schüler, F, Seeger, K, Seelig, R, Thiede, C, Viehmann, S, Weber, C, Wilhelm, S, Christmann, A, Clement, JH, Ebener, U, Enczmann, J, Leo, R, Schleuning, M, Schoch, R, and Thiel, E

Published
2000
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39. Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification—an approach to classification of patients with t-MDS

Author

Kuendgen, A., primary, Nomdedeu, M., additional, Tuechler, H., additional, Garcia-Manero, G., additional, Komrokji, R. S., additional, Sekeres, M. A., additional, Della Porta, M. G., additional, Cazzola, M., additional, DeZern, A. E., additional, Roboz, G. J., additional, Steensma, D. P., additional, Van de Loosdrecht, A. A., additional, Schlenk, R. F., additional, Grau, J., additional, Calvo, X., additional, Blum, S., additional, Pereira, A., additional, Valent, P., additional, Costa, D., additional, Giagounidis, A., additional, Xicoy, B., additional, Döhner, H., additional, Platzbecker, U., additional, Pedro, C., additional, Lübbert, M., additional, Oiartzabal, I., additional, Díez-Campelo, M., additional, Cedena, M. T., additional, Machherndl-Spandl, S., additional, López-Pavía, M., additional, Baldus, C. D., additional, Martinez-de-Sola, M., additional, Stauder, R., additional, Merchan, B., additional, List, A., additional, Ganster, C., additional, Schroeder, T., additional, Voso, M. T., additional, Pfeilstöcker, M., additional, Sill, H., additional, Hildebrandt, B., additional, Esteve, J., additional, Nomdedeu, B., additional, Cobo, F., additional, Haas, R., additional, Sole, F., additional, Germing, U., additional, Greenberg, P. L., additional, Haase, D., additional, and Sanz, G., additional

Published
2020
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42. Impact of salvage regimens on response and overall survival in acute myeloid leukemia with induction failure

Author

Heinz-August Horst, Jürgen Krauter, Axel Benner, Verena I. Gaidzik, Andrea Kündgen, Hans-Juergen Salwender, Thomas Kindler, R.F. Schlenk, Helmut R. Salih, M. Wattad, Peter Paschka, Peter Brossart, Felicitas Thol, Claus-Henning Köhne, Daniela Weber, Hartmut Döhner, Michael Lübbert, David Nachbaur, Arnold Ganser, Michael Heuser, Mark Ringhoffer, Konstanze Döhner, Gerhard Held, Gerald Wulf, and Katharina Götze

Subjects
Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Adolescent, Gemtuzumab ozogamicin, Salvage therapy, Young Adult, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Transplantation, Homologous, Idarubicin, Prospective Studies, Survival rate, Aged, Neoplasm Staging, Aged, 80 and over, Salvage Therapy, Mitoxantrone, business.industry, Remission Induction, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Hematology, Middle Aged, Prognosis, Combined Modality Therapy, Surgery, Survival Rate, Transplantation, Leukemia, Myeloid, Acute, 030220 oncology & carcinogenesis, Cytarabine, Female, Neoplasm Recurrence, Local, business, Follow-Up Studies, 030215 immunology, medicine.drug
Abstract

We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients with newly diagnosed AML were enrolled in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. In addition, 180 patients, although responding to first induction, relapsed after second induction therapy. Of the 1025 patients with induction failure, 875 (median age 55 years) received intensive salvage therapy: 7+3-based (n=59), high-dose cytarabine combined with mitoxantrone (HAM; n=150), with all-trans retinoic acid (A; A-HAM) (n=247), with gemtuzumab ozogamicin and A (GO; GO-A-HAM) (n=140), other intensive regimens (n=165), experimental treatment (n=27) and direct allo-HCT (n=87). In patients receiving intensive salvage chemotherapy (n=761), response (complete remission/complete remission with incomplete hematological recovery (CR/CRi)) was associated with GO-A-HAM treatment (odds ratio (OR), 1.93; P=0.002), high-risk cytogenetics (OR, 0.62; P=0.006) and age (OR for a 10-year difference, 0.75; P

Published
2017
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44. Functional and clinical characterization of the alternatively spliced isoform AML1-ETO9a in adult patients with translocation t(8;21)(q22;q22.1) acute myeloid leukemia (AML)

Author

Mohammed Wattad, Daniela Weber, Arnold Ganser, Felicitas Thol, Nikolaus Jahn, Frank G. Rücker, Ivan Bedzhov, Mridul Agrawal, Elisabeth Koller, Franz Oswald, Thomas Schroeder, Peggy Schwarz, Peter Paschka, Hartmut Döhner, Thomas Kindler, Katharina Götze, Mark Ringhoffer, Tilman Borggrefe, Michael Heuser, Konstanze Döhner, Verena I. Gaidzik, Hans Salwender, Benedetto Daniele Giaimo, Elisabeth Lange, Hartmut Geiger, Andrea Corbacioglu, Michael Lübbert, and Lars Bullinger

Subjects
Gene isoform, Adult, Male, Cancer Research, Myeloid, Letter, Oncogene Proteins, Adolescent, Oncogene Proteins, Fusion, Chromosomes, Human, Pair 21, Chromosomal translocation, Translocation, Genetic, Young Adult, RUNX1 Translocation Partner 1 Protein, medicine, Humans, Protein Isoforms, Young adult, Oncogenesis, Aged, business.industry, Myeloid leukemia, Hematology, Oncogenes, Middle Aged, medicine.disease, ddc, Leukemia, Alternative Splicing, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, Core Binding Factor Alpha 2 Subunit, Cancer research, Female, T(8, 21)(q22, q22), business, Chromosomes, Human, Pair 8
Published
2019

45. Erratum: Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia

Author

Madan, V, Shyamsunder, P, Han, L, Mayakonda, A, Nagata, Y, Sundaresan, J, Kanojia, D, Yoshida, K, Ganesan, S, Hattori, N, Fulton, N, Tan, K T, Alpermann, T, Kuo, M C, Rostami, S, Matthews, J, Sanada, M, Liu, L-Z, Shiraishi, Y, Miyano, S, Chendamarai, E, Hou, H A, Malnassy, G, Ma, T, Garg, M, Ding, L W, Sun, Q Y, Chien, W, Ikezoe, T, Lill, M, Biondi, A, Larson, R A, Powell, B L, Lübbert, M, Chng, W J, Tien, H F, Heuser, M, Ganser, A, Koren-Michowitz, M, Kornblau, S M, Kantarjian, H M, Nowak, D, Hofmann, W K, Yang, H, Stock, W, Ghavamzadeh, A, Alimoghaddam, K, Haferlach, T, Ogawa, S, Shih, L Y, Mathews, V, and Koeffler, H P

Published
2016
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48. Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis

Author

Bernd Hertenstein, M. Wattad, Jürgen Krauter, Peter Paschka, Gesine Bug, Gerhard Heil, Lars Bullinger, Jana Fabisch, Walter Fiedler, Verena I. Gaidzik, Hartmut Döhner, Sabrina Klesse, Arnold Ganser, Hartmut Kirchner, Brigitte Schlegelberger, Felicitas Thol, Alessandro Liebich, Arnold Kloos, Michael Heuser, Hubert Serve, Gudrun Göhring, Razif Gabdoulline, Anuhar Chaturvedi, Doris Kraemer, Richard F. Schlenk, L Köhler, Martin Wichmann, Konstanze Döhner, and Michael Lübbert

Subjects
Male, 0301 basic medicine, Cancer Research, Myeloid, medicine.medical_treatment, Clone (cell biology), Hematopoietic stem cell transplantation, DNA Methyltransferase 3A, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Medicine, DNA (Cytosine-5-)-Methyltransferases, Aged, 80 and over, Hematopoietic Stem Cell Transplantation, High-Throughput Nucleotide Sequencing, Myeloid leukemia, Hematology, Lymphoid Progenitor Cells, Middle Aged, Prognosis, Combined Modality Therapy, 3. Good health, Survival Rate, Leukemia, Myeloid, Acute, Leukemia, Haematopoiesis, medicine.anatomical_structure, Oncology, RUNX1, 030220 oncology & carcinogenesis, Female, Adult, Adolescent, Article, Young Adult, 03 medical and health sciences, Biomarkers, Tumor, Humans, Myeloid Progenitor Cells, Aged, Neoplasm Staging, business.industry, Myelodysplastic syndromes, medicine.disease, Clone Cells, Hematopoiesis, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Mutation, Immunology, Cancer research, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract

We studied acute myeloid leukemia (AML) patients with lympho-myeloid clonal hematopoiesis (LM-CH), defined by the presence of DNA methyltransferase 3A (DNMT3A) mutations in both the myeloid and lymphoid T-cell compartment. Diagnostic, complete remission (CR) and relapse samples were sequenced for 34 leukemia-related genes in 171 DNMT3A mutated adult AML patients. AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2). In 82% of AML patients with LM-CH, the preleukemic clone was refractory to chemotherapy and was the founding clone for relapse. Both LM-CH and non-LM-CH MRD-positive AML patients who achieved CR had a high risk of relapse after 10 years (75% and 75%, respectively) compared with patients without clonal hematopoiesis in CR with negative MRD (27% relapse rate). Long-term survival of patients with LM-CH was only seen after allogeneic hematopoietic stem cell transplantation (HSCT). We define AML patients with LM-CH as a distinct high-risk group of AML patients that can be identified at diagnosis through mutation analysis in T cells and should be considered for HSCT.

Published
2016
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49. Allogeneic hematopoietic cell transplantation with double alkylating agents containing reduced-intensity conditioning for patients ⩾60 years with advanced AML/MDS

Author

Ralph Wäsch, Jürgen Finke, Reinhard Marks, Michael Lübbert, Hartmut Bertz, Robert Zeiser, and Kristin Ohneberg

Subjects
Male, Cancer Research, medicine.medical_specialty, Transplantation Conditioning, Myeloid, Graft vs Host Disease, 03 medical and health sciences, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Transplantation, Homologous, Antineoplastic Agents, Alkylating, Aged, Hematology, business.industry, Hematopoietic Stem Cell Transplantation, Middle Aged, medicine.disease, Survival Analysis, Lymphoma, Transplantation, Leukemia, Myeloid, Acute, Haematopoiesis, Leukemia, Treatment Outcome, medicine.anatomical_structure, Oncology, Myelodysplastic Syndromes, 030220 oncology & carcinogenesis, Immunology, Cancer research, Female, Stem cell, business, 030215 immunology
Abstract

Allogeneic hematopoietic cell transplantation with double alkylating agents containing reduced-intensity conditioning for patients ⩾ 60 years with advanced AML/MDS

Published
2016
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50. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia

Author

Michael Heuser, Manoj Garg, T Haferlach, L. Z. Liu, Shih Ly, Yuichi Shiraishi, Takayuki Ikezoe, Michael Lill, Hwei-Fang Tien, Henry Yang, Ling-Wen Ding, Hagop M. Kantarjian, H P Koeffler, T. Ma, Yasunobu Nagata, Wolf-K. Hofmann, Qiao-Yang Sun, Satoru Miyano, Richard A. Larson, Noreen Fulton, Seishi Ogawa, Pavithra Shyamsunder, Masashi Sanada, Kamran Alimoghaddam, W. J. Chng, Norimichi Hattori, Saravanan Ganesan, Wendy Stock, Tamara Alpermann, S. Rostami, Ezhilarasi Chendamarai, Vikram Mathews, Kenichi Yoshida, Anand Mayakonda, Steve Kornblau, M. C. Kuo, Gregory Malnassy, Vikas Madan, Lin Han, A. Ghavamzadeh, Hsin-An Hou, Andrea Biondi, Bayard L. Powell, W. Chien, Jairo Matthews, Janani Sundaresan, Michael Lübbert, Daniel Nowak, Deepika Kanojia, Arnold Ganser, Kar Tong Tan, Maya Koren-Michowitz, Madan, V, Shyamsunder, P, Han, L, Mayakonda, A, Nagata, Y, Sundaresan, J, Kanojia, D, Yoshida, K, Ganesan, S, Hattori, N, Fulton, N, Tan, K, Alpermann, T, Kuo, M, Rostami, S, Matthews, J, Sanada, M, Liu, L, Shiraishi, Y, Miyano, S, Chendamarai, E, Hou, H, Malnassy, G, Ma, T, Garg, M, Ding, L, Sun, Q, Chien, W, Ikezoe, T, Lill, M, Biondi, A, Larson, R, Powell, B, Lubbert, M, Chng, W, Tien, H, Heuser, M, Ganser, A, Koren-Michowitz, M, Kornblau, S, Kantarjian, H, Nowak, D, Hofmann, W, Yang, H, Stock, W, Ghavamzadeh, A, Alimoghaddam, K, Haferlach, T, Ogawa, S, Shih, L, Mathews, V, and Koeffler, H

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Acute promyelocytic leukemia, Cancer Research, ARID1A, DNA-Binding Protein, DNA Mutational Analysis, Clinical Sciences, Oncology and Carcinogenesis, Immunology, Acute, Biology, DNA Mutational Analysi, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, Recurrence, immune system diseases, medicine, Humans, Exome, neoplasms, Nuclear Protein, Promyelocytic, Genetics, Leukemia, Gene Expression Profiling, Nuclear Proteins, Myeloid leukemia, Cell Differentiation, Hematology, medicine.disease, DNA-Binding Proteins, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Original Article, Human, Transcription Factors
Abstract

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Published
2016
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