132 results on '"Kuchenbauer F"'
Search Results
2. MicroRNA-155 promotes G-CSF-induced mobilization of murine hematopoietic stem and progenitor cells via propagation of CXCL12 signaling
- Author
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Itkin, T, Kumari, A, Schneider, E, Gur-Cohen, S, Ludwig, C, Brooks, R, Kollet, O, Golan, K, Khatib-Massalha, E, Russo, C M, Chisholm, J D, Rouhi, A, Geiger, H, Hornstein, E, Kerr, W G, Kuchenbauer, F, and Lapidot, T
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- 2017
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3. Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice
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Staffas, A, Arabanian, L S, Wei, S Y, Jansson, A, Ståhlman, S, Johansson, P, Fogelstrand, L, Cammenga, J, Kuchenbauer, F, and Palmqvist, L
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- 2017
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4. RNA interference efficiently targets human leukemia driven by a fusion oncogene in vivo
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Jyotsana, N, Sharma, A, Chaturvedi, A, Scherr, M, Kuchenbauer, F, Sajti, L, Barchanski, A, Lindner, R, Noyan, F, Sühs, K-W, Grote-Koska, D, Brand, K, Vornlocher, H-P, Stanulla, M, Bornhauser, B, Bourquin, J-P, Eder, M, Thol, F, Ganser, A, Humphries, R K, Ramsay, E, Cullis, P, and Heuser, M
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- 2018
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5. P542: REAL WORLD OUTCOMES FOR PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA IN BRITISH COLUMBIA (BC): EXCELLENT OUTCOMES WITH LOW EARLY DEATH RATE AND HIGH OVERALL SURVIVAL IN A POPULATION BASED STUDY
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Henderson, R., primary, Eissa, Y., additional, Stubbins, R., additional, Abou Mourad, Y., additional, Chung, S., additional, Forrest, D., additional, Hay, K., additional, Kuchenbauer, F., additional, Nantel, S., additional, Nevill, T., additional, Power, M., additional, Rodrigo, J., additional, Roy, C., additional, Sanford, D., additional, Song, K., additional, Sutherland, H., additional, Toze, C., additional, White, J., additional, and Narayanan, S., additional
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- 2022
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6. Constitutive IRF8 expression inhibits AML by activation of repressed immune response signaling
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Sharma, A, Yun, H, Jyotsana, N, Chaturvedi, A, Schwarzer, A, Yung, E, Lai, C K, Kuchenbauer, F, Argiropoulos, B, Görlich, K, Ganser, A, Humphries, R K, and Heuser, M
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- 2015
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7. Comprehensive microRNA expression profiling of the hematopoietic hierarchy
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Petriv, O. I., Kuchenbauer, F., Delaney, A. D., Lecault, V., White, A., Kent, D., Marmolejo, L., Heuser, M., Berg, T., Copley, M., Ruschmann, J., Sekulovic, S., Benz, C., Kuroda, E., Ho, V., Antignano, F., Halim, T., Giambra, V., Krystal, G., Takei, C. J. F., Weng, A. P., Piret, J., Eaves, C., Marra, M. A., Humphries, R. K., Hansen, C. L., and Hood, Leroy E.
- Published
- 2010
8. Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia
- Author
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Allegra, D, Bilan, V, Garding, A, Döhner, H, Stilgenbauer, S, Kuchenbauer, F, and Mertens, D
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- 2014
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9. Functional role of BAALC in leukemogenesis
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Heuser, M, Berg, T, Kuchenbauer, F, Lai, C K, Park, G, Fung, S, Lin, G, Leung, M, Krauter, J, Ganser, A, and Humphries, R K
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- 2012
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10. The long non-coding RNA Cancer Susceptibility 15 (CASC15) is induced by isocitrate dehydrogenase (IDH) mutations and maintains an immature phenotype in adult acute myeloid leukemia
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Grasedieck, S., Ruess, C., Krowiorz, K., Lux, S., Pochert, N., Schwarzer, A., Klusmann, J., Jongen-Lavrencic, M., Herold, T., Bullinger, L., Pollack, J.R., Rouhi, A., Kuchenbauer, F., and Hematology
- Subjects
Adult ,Leukemia, Myeloid, Acute ,Phenotype ,SDG 3 - Good Health and Well-being ,Mutation ,Humans ,RNA, Long Noncoding ,Letters to the Editor ,Isocitrate Dehydrogenase - Published
- 2020
11. A rare case of acute myeloid leukemia with a CHIC2-ETV6 fusiongen and multiple other molecular aberrations
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Kuchenbauer, F, Schoch, C, Holler, E, Haferlach, T, Hiddemann, W, and Schnittger, S
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- 2005
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12. Erratum: Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia
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Allegra, D, Bilan, V, Garding, A, Zucknick, M, Döhner, H, Stilgenbauer, S, Kuchenbauer, F, and Mertens, D
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- 2014
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13. PS1542 RESPIRATORY SYNCYTIAL VIRUS AND HUMAN METAPNEUMOVIRUS INFECTIONS AFTER ALLOGENEIC STEM CELL TRANSPLANTATION: IMPACT OF THE IMMUNODEFICIENCY SCORING INDEX AND RIBAVIRIN TREATMENT ON THE OUTCOMES
- Author
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Akhmedov, M., primary, Wais, V., additional, Sala, E., additional, Neagoie, A., additional, Gantner, A., additional, von Harsdorf, S., additional, Kuchenbauer, F., additional, Schubert, A., additional, Michael, D., additional, Döhner, H., additional, and Bunjes, D., additional
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- 2019
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14. PF208 MN1 IS INDISPENSABLE FOR MLL-REARRANGED ACUTE MYELOID LEUKEMIA
- Author
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Sharma, A., primary, Jyotsana, N., additional, Gabdoulline, R., additional, Heckl, D., additional, Kuchenbauer, F., additional, Slany, R., additional, Ganser, A., additional, and Heuser, M., additional
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- 2019
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15. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells
- Author
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Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., Antin, J.H., et al., Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., and Antin, J.H., et al.
- Abstract
Contains fulltext : 190745.pdf (publisher's version ) (Closed access), Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.
- Published
- 2018
16. Endogenous tumor suppressor microRNA-193b: Therapeutic and prognostic value in acute myeloid leukemia
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Bhayadia, R. (Raj), Krowiorz, K. (Kathrin), Haetscher, N. (Nadine), Jammal, R. (Razan), Emmrich, S. (Stephan), Obulkasim, A. (Askar), Fiedler, J. (Jan), Schwarzer, A. (Adrian), Rouhi, A. (Arefeh), Heuser, M. (Michael), Wingert, S. (Susanne), Bothur, S. (Sabrina), Döhner, K. (Konstanze), Mätzig, T. (Tobias), Ng, M. (Michelle), Reinhardt, D. (Dirk), Döhner, H. (Hartmut), Zwaan, C.M. (Michel), Heuvel-Eibrink, M.M. (Marry) van den, Heckl, D. (Dirk), Fornerod, M.W.J. (Maarten), Thum, T. (Thomas), Humphries, R.K. (R. Keith), Rieger, M.A. (Michael A.), Kuchenbauer, F. (Florian), Klusmann, J.-H., Bhayadia, R. (Raj), Krowiorz, K. (Kathrin), Haetscher, N. (Nadine), Jammal, R. (Razan), Emmrich, S. (Stephan), Obulkasim, A. (Askar), Fiedler, J. (Jan), Schwarzer, A. (Adrian), Rouhi, A. (Arefeh), Heuser, M. (Michael), Wingert, S. (Susanne), Bothur, S. (Sabrina), Döhner, K. (Konstanze), Mätzig, T. (Tobias), Ng, M. (Michelle), Reinhardt, D. (Dirk), Döhner, H. (Hartmut), Zwaan, C.M. (Michel), Heuvel-Eibrink, M.M. (Marry) van den, Heckl, D. (Dirk), Fornerod, M.W.J. (Maarten), Thum, T. (Thomas), Humphries, R.K. (R. Keith), Rieger, M.A. (Michael A.), Kuchenbauer, F. (Florian), and Klusmann, J.-H.
- Abstract
Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo. Results miR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio 6 standard error, 20.56 6 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR-193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1. Conclusion The tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms.
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- 2018
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17. Endogenous Tumor Suppressor microRNA-193b: Therapeutic and Prognostic Value in Acute Myeloid Leukemia
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Bhayadia, R, Krowiorz, K, Haetscher, N, Jammal, R, Emmrich, S, Obulkasim, Askar, Fiedler, J, Schwarzer, A, Rouhi, A, Heuser, M, Wingert, S, Bothur, S, Dohner, K, Matzig, T, Ng, M, Reinhardt, D, Dohner, H, Zwaan, C.M., Van den Heuvel - Eibrink, Marry, Heckl, D, Fornerod, M.W.J., Thum, T, Humphries, RK, Rieger, MA, Kuchenbauer, F, Klusmann, JH, Bhayadia, R, Krowiorz, K, Haetscher, N, Jammal, R, Emmrich, S, Obulkasim, Askar, Fiedler, J, Schwarzer, A, Rouhi, A, Heuser, M, Wingert, S, Bothur, S, Dohner, K, Matzig, T, Ng, M, Reinhardt, D, Dohner, H, Zwaan, C.M., Van den Heuvel - Eibrink, Marry, Heckl, D, Fornerod, M.W.J., Thum, T, Humphries, RK, Rieger, MA, Kuchenbauer, F, and Klusmann, JH
- Published
- 2018
18. Circular RNAs of the nucleophosmin (NPM1) gene in acute myeloid leukemia
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Hirsch, S. (Susanne), Blätte, T.J. (Tamara J.), Grasedieck, S. (Sarah), Cocciardi, S. (Sibylle), Rouhi, A. (Arefeh), Jongen-Lavrencic, M. (Mojca), Paschka, P. (Peter), Krönke, J. (Jan), Gaidzik, V.I. (Verena), Döhner, H. (Hartmut), Schlenk, R.F. (Richard), Kuchenbauer, F. (Florian), Döhner, K. (Konstanze), Dolnik, A. (Anna), Bullinger, L. (Lars), Hirsch, S. (Susanne), Blätte, T.J. (Tamara J.), Grasedieck, S. (Sarah), Cocciardi, S. (Sibylle), Rouhi, A. (Arefeh), Jongen-Lavrencic, M. (Mojca), Paschka, P. (Peter), Krönke, J. (Jan), Gaidzik, V.I. (Verena), Döhner, H. (Hartmut), Schlenk, R.F. (Richard), Kuchenbauer, F. (Florian), Döhner, K. (Konstanze), Dolnik, A. (Anna), and Bullinger, L. (Lars)
- Abstract
In acute myeloid leukemia, there is growing evidence for splicing pattern deregulation, including differential expression of linear splice isoforms of the commonly mutated gene nucleophosmin (NPM1). In this study, we detect circular RNAs of NPM1 and quantify circRNA hsa_circ_0075001 in a cohort of NPM1 wild-type and mutated acute myeloid leukemia (n=46). Hsa_circ_0075001 expression correlates positively with total NPM1 expression, but is independent of the NPM1 mutational status. High versus low hsa_circ_0075001 expression defines patient subgroups characterized by distinct gene expression patterns, such as lower expression of components of the Toll-like receptor signaling pathway in high hsa_circ_0075001 expression cases. Global evaluation of circRNA expression in sorted healthy hematopoietic controls (n=10) and acute myeloid leukemia (n=10) reveals circRNA transcripts for 47.9% of all highly expressed genes. While circRNA expression correlates globally with parental gene expression, we identify hematopoietic differentiation-associated as well as acute myeloid leukemia subgroup-specific circRNA signatures.
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- 2017
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19. The non-coding RNA landscape of human hematopoiesis and leukemia
- Author
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Schwarzer, A. (Adrian), Emmrich, S. (Stephan), Schmidt, F. (Franziska), Beck, D. (Dominik), Ng, M. (Michelle), Reimer, C. (Christina), Adams, F.F. (Felix Ferdinand), Grasedieck, S. (Sarah), Witte, D. (Damian), Käbler, S. (Sebastian), Wong, J.W.H. (Jason W.H.), Shah, A. (Anushi), Huang, Y. (Yizhou), Jammal, R. (Razan), Maroz, A. (Aliaksandra), Jongen-Lavrencic, M. (Mojca), Schambach, A. (Axel), Kuchenbauer, F. (Florian), Pimanda, J.E. (John), Reinhardt, D. (Dirk), Heckl, D. (Dirk), Klusmann, J.-H., Schwarzer, A. (Adrian), Emmrich, S. (Stephan), Schmidt, F. (Franziska), Beck, D. (Dominik), Ng, M. (Michelle), Reimer, C. (Christina), Adams, F.F. (Felix Ferdinand), Grasedieck, S. (Sarah), Witte, D. (Damian), Käbler, S. (Sebastian), Wong, J.W.H. (Jason W.H.), Shah, A. (Anushi), Huang, Y. (Yizhou), Jammal, R. (Razan), Maroz, A. (Aliaksandra), Jongen-Lavrencic, M. (Mojca), Schambach, A. (Axel), Kuchenbauer, F. (Florian), Pimanda, J.E. (John), Reinhardt, D. (Dirk), Heckl, D. (Dirk), and Klusmann, J.-H.
- Abstract
Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.
- Published
- 2017
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20. Circular RNAs of the nucleophosmin (NPM1) gene in acute myeloid leukemia
- Author
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Hirsch, S, Blatte, TJ, Grasedieck, S, Cocciardi, S, Rouhi, A, Jongen - Lavrencic, Mojca, Paschka, P, Kronke, J, Gaidzik, VI, Dohner, H, Schlenk, RF, Kuchenbauer, F, Dohner, K, Dolnik, A, Bullinger, L, Hirsch, S, Blatte, TJ, Grasedieck, S, Cocciardi, S, Rouhi, A, Jongen - Lavrencic, Mojca, Paschka, P, Kronke, J, Gaidzik, VI, Dohner, H, Schlenk, RF, Kuchenbauer, F, Dohner, K, Dolnik, A, and Bullinger, L
- Published
- 2017
21. The non-coding RNA landscape of human hematopoiesis and leukemia
- Author
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Schwarzer, A, Emmrich, S, Schmidt, F, Beck, D, Ng, M, Reimer, C, Adams, FF, Grasedieck, S, de Witte, DH, Kabler, S, Wong, JWH, Shah, A, Huang, YZ, Jammal, R, Maroz, A, Jongen - Lavrencic, Mojca, Schambach, A, Kuchenbauer, F, Pimanda, JE, Reinhardt, D, Heck, D, Klusmann, JH, Schwarzer, A, Emmrich, S, Schmidt, F, Beck, D, Ng, M, Reimer, C, Adams, FF, Grasedieck, S, de Witte, DH, Kabler, S, Wong, JWH, Shah, A, Huang, YZ, Jammal, R, Maroz, A, Jongen - Lavrencic, Mojca, Schambach, A, Kuchenbauer, F, Pimanda, JE, Reinhardt, D, Heck, D, and Klusmann, JH
- Published
- 2017
22. Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice
- Author
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Staffas, A., Arabanian, L. S., Wei, S. Y., Jansson, A., Stahlman, S., Johansson, P., Fogelstrand, L., Cammenga, Jörg, Kuchenbauer, F., Palmqvist, L., Staffas, A., Arabanian, L. S., Wei, S. Y., Jansson, A., Stahlman, S., Johansson, P., Fogelstrand, L., Cammenga, Jörg, Kuchenbauer, F., and Palmqvist, L.
- Abstract
HOXA9, MEIS1 and FLT3 are genes frequently upregulated in human acute myeloid leukemia. Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis. To define the role of Flt3 in AML with high Hoxa9/Meis1, we treated mice with Hoxa9/Meis1-induced AML with the Flt3 inhibitor AC220, used an Flt3-ligand (FL -/-) knockout model, and investigated whether overexpression of Flt3 could induce leukemia together with overexpression of Hoxa9. Flt3 inhibition by AC220 did not delay AML development in mice transplanted with bone marrow cells overexpressing Hoxa9 and Meis1. In addition, Hoxa9/Meis1 cells induced AML in FL -/- mice as rapid as in wild-type mice. However, FL -/- mice had reduced organ infiltration compared with wild-type mice, suggesting some Flt3 dependent effect on leukemic invasiveness. Interestingly, leukemic Hoxa9/Meis1 cells from sick mice expressed high levels of Flt3 regardless of presence of its ligand, showing that Flt3 is a passive marker on these cells. In line with this, combined engineered overexpression of Flt3 and Hoxa9 did not accelerate the progression to AML. We conclude that the Hoxa9- and Meis1-associated upregulation of Flt3 is not a requirement for leukemic progression induced by Hoxa9 and Meis1., Funding Agencies|Swedish Cancer Society [CAN2014/525]; Vastra Gotalandsregionen [ALFGBG-431881]; Deutsche Krebshilfe [109420]; European Hematology Association; Deutsche Forschungsgemeinschaft [SFB 1074]; Assar Gabrielssons foundation
- Published
- 2017
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23. RNA interference efficiently targets human leukemia driven by a fusion oncogene in vivo
- Author
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Jyotsana, N, primary, Sharma, A, additional, Chaturvedi, A, additional, Scherr, M, additional, Kuchenbauer, F, additional, Sajti, L, additional, Barchanski, A, additional, Lindner, R, additional, Noyan, F, additional, Sühs, K-W, additional, Grote-Koska, D, additional, Brand, K, additional, Vornlocher, H-P, additional, Stanulla, M, additional, Bornhauser, B, additional, Bourquin, J-P, additional, Eder, M, additional, Thol, F, additional, Ganser, A, additional, Humphries, R K, additional, Ramsay, E, additional, Cullis, P, additional, and Heuser, M, additional
- Published
- 2017
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24. IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM)
- Author
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Krönke, J, primary, Kuchenbauer, F, additional, Kull, M, additional, Teleanu, V, additional, Bullinger, L, additional, Bunjes, D, additional, Greiner, A, additional, Kolmus, S, additional, Köpff, S, additional, Schreder, M, additional, Mügge, L-O, additional, Straka, C, additional, Engelhardt, M, additional, Döhner, H, additional, Einsele, H, additional, Bassermann, F, additional, Bargou, R, additional, Knop, S, additional, and Langer, C, additional
- Published
- 2016
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25. MiR-139-5p is a potent tumor suppressor in adult acute myeloid leukemia
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Krowiorz, K, primary, Ruschmann, J, additional, Lai, C, additional, Ngom, M, additional, Maetzig, T, additional, Martins, V, additional, Scheffold, A, additional, Schneider, E, additional, Pochert, N, additional, Miller, C, additional, Palmqvist, L, additional, Staffas, A, additional, Mulaw, M, additional, Bohl, S R, additional, Buske, C, additional, Heuser, M, additional, Kraus, J, additional, O'Neill, K, additional, Hansen, C L, additional, Petriv, O I, additional, Kestler, H, additional, Döhner, H, additional, Bullinger, L, additional, Döhner, K, additional, Humphries, R K, additional, Rouhi, A, additional, and Kuchenbauer, F, additional
- Published
- 2016
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26. Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice
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Staffas, A, primary, Arabanian, L S, additional, Wei, S Y, additional, Jansson, A, additional, Ståhlman, S, additional, Johansson, P, additional, Fogelstrand, L, additional, Cammenga, J, additional, Kuchenbauer, F, additional, and Palmqvist, L, additional
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- 2016
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27. MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia
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Gentner, B. (Bernhard), Pochert, N. (Nicole), Rouhi, A. (Arefeh), Boccalatte, F. (Francesco), Plati, T. (Tiziana), Berg, T. (Tobias), Sun, S.M. (Su Ming), Mah, S.M. (Sarah M.), Mirkovic-Hösle, M. (Milijana), Ruschmann, J. (Jens), Muranyi, A. (Andrew), Leierseder, S. (Simon), Argiropoulos, B. (Bob), Starczynowski, D.T. (Daniel T.), Karsan, A. (Aly), Heuser, M. (Michael), Hogge, D. (Donna), Camargo, F.D. (Fernando D.), Engelhardt, S. (Stefan), Döhner, H. (Hartmut), Buske, C. (Christian), Jongen-Lavrencic, M. (Mojca), Naldini, L. (Luigi), Humphries, R.K. (R. Keith), Kuchenbauer, F. (Florian), Gentner, B. (Bernhard), Pochert, N. (Nicole), Rouhi, A. (Arefeh), Boccalatte, F. (Francesco), Plati, T. (Tiziana), Berg, T. (Tobias), Sun, S.M. (Su Ming), Mah, S.M. (Sarah M.), Mirkovic-Hösle, M. (Milijana), Ruschmann, J. (Jens), Muranyi, A. (Andrew), Leierseder, S. (Simon), Argiropoulos, B. (Bob), Starczynowski, D.T. (Daniel T.), Karsan, A. (Aly), Heuser, M. (Michael), Hogge, D. (Donna), Camargo, F.D. (Fernando D.), Engelhardt, S. (Stefan), Döhner, H. (Hartmut), Buske, C. (Christian), Jongen-Lavrencic, M. (Mojca), Naldini, L. (Luigi), Humphries, R.K. (R. Keith), and Kuchenbauer, F. (Florian)
- Abstract
A precise understanding of the role of miR-223 in human hematopoiesis and in the pathogenesis of acute myeloid leukemia (AML) is still lacking. By measuring miR-223 expression in blasts from 115 AML patients, we found significantly higher miR-223 levels in patients with favorable prognosis, whereas patients with low miR-223 expression levels were associated with worse outcome. Furthermore, miR-223 was hierarchically expressed in AML subpopulations, with lower expression in leukemic stem cell-containing fractions. Genetic depletion of miR-223 decreased the leukemia initiating cell (LIC) frequency in a myelomonocytic AML mouse model, but it was not mandatory for rapid-onset AML. To relate these observations to physiologic myeloid differentiation, we knocked down or ectopically expressed miR-223 in cord-blood CD34+ cells using lentiviral vectors. Although miR-223 knockdown delayed myeloerythroid precursor differentiation in vitro, it increased myeloid progenitors in vivo following serial xenotransplantation. Ectopic miR-223 expression increased erythropoiesis, T lymphopoiesis, and early B lymphopoiesis in vivo. These findings broaden the role of miR-223 as a regulator of the expansion/differentiation equilibrium in hematopoietic stem and progenitor cells where its impact is dose- and differentiation-stage-dependent. This also explains the complex yet minor role of miR-223 in AML, a heterogeneous disease with variable degree of myeloid differentiation.
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- 2015
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28. Constitutive IRF8 expression inhibits AML by activation of repressed immune response signaling
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Sharma, A, primary, Yun, H, additional, Jyotsana, N, additional, Chaturvedi, A, additional, Schwarzer, A, additional, Yung, E, additional, Lai, C K, additional, Kuchenbauer, F, additional, Argiropoulos, B, additional, Görlich, K, additional, Ganser, A, additional, Humphries, R K, additional, and Heuser, M, additional
- Published
- 2014
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29. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin
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Morin, R., Johnson, N., Severson, T., Mungall, A., An, J., Goya, R., Paul, J., Boyle, M., Woolcock, B., Kuchenbauer, F., Yap, D., Humphries, R., Griffith, O., Shah, S., Zhu, H., Kimbara, M., Shashkin, P., Charlot, J., Tcherpakov, M., Corbett, R., Tam, A., Varhol, Richard, Smailus, D., Moksa, M., Zhao, Y., Delaney, A., Qian, H., Birol, I., Schein, J., Moore, R., Holt, R., Horsman, D., Connors, J., Jones, S., Aparicio, S., Hirst, M., Gascoyne, R., Marra, M., Morin, R., Johnson, N., Severson, T., Mungall, A., An, J., Goya, R., Paul, J., Boyle, M., Woolcock, B., Kuchenbauer, F., Yap, D., Humphries, R., Griffith, O., Shah, S., Zhu, H., Kimbara, M., Shashkin, P., Charlot, J., Tcherpakov, M., Corbett, R., Tam, A., Varhol, Richard, Smailus, D., Moksa, M., Zhao, Y., Delaney, A., Qian, H., Birol, I., Schein, J., Moore, R., Holt, R., Horsman, D., Connors, J., Jones, S., Aparicio, S., Hirst, M., Gascoyne, R., and Marra, M.
- Abstract
Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-B pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.
- Published
- 2010
30. Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia
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Allegra, D, primary, Bilan, V, additional, Garding, A, additional, Döhner, H, additional, Stilgenbauer, S, additional, Kuchenbauer, F, additional, and Mertens, D, additional
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- 2013
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31. IKZF1expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM)
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Krönke, J, Kuchenbauer, F, Kull, M, Teleanu, V, Bullinger, L, Bunjes, D, Greiner, A, Kolmus, S, Köpff, S, Schreder, M, Mügge, L-O, Straka, C, Engelhardt, M, Döhner, H, Einsele, H, Bassermann, F, Bargou, R, Knop, S, and Langer, C
- Abstract
Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSGmRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1expression had a superior PFS compared with patients in the remaining quartiles (Q2–Q4; 3-year PFS of 86 vs 51%, P=0.01). This translated into a significant better overall survival (100 vs 74%, P=0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3and BSGexpression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSGexpression levels in lenalidomide-treated multiple myeloma.
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- 2017
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32. Functional role of BAALC in leukemogenesis
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Heuser, M, primary, Berg, T, additional, Kuchenbauer, F, additional, Lai, C K, additional, Park, G, additional, Fung, S, additional, Lin, G, additional, Leung, M, additional, Krauter, J, additional, Ganser, A, additional, and Humphries, R K, additional
- Published
- 2011
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33. Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix
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Paez-Pereda, M., primary, Kuchenbauer, F., additional, Arzt, E., additional, and Stalla, G.K., additional
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- 2005
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34. The role of donor clonal hematopoiesis in allogeneic hematopoietic stem cell transplantation
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Frick, M., Chan, W., Arends, C. M., Hablesreiter, R., Halik, A., Blau, O., Heuser, M., David Michonneau, Galan-Sousa, J., Noerenberg, D., Wais, V., Stadler, M., Yoshida, K., Schetelig, J., Schuler, E., Thol, F., Clappier, E., Christopeit, M., Ayuk, F. A., Bornhaeuser, M., Blau, I. W., Ogawa, S., Zemojtel, T., Gerbitz, A., Spriewald, B. M., Schrezenmeier, H., Kuchenbauer, F., Kobbe, G., Wiesneth, M., Koldehoff, M., Socie, G., Kroeger, N., Bullinger, L., Thiede, C., and Damm, F.
- Subjects
Medizin
35. MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia
- Author
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Simon Leierseder, Arefeh Rouhi, Andrew L Muranyi, Stefan Engelhardt, Francesco Boccalatte, Jens Ruschmann, Daniel T. Starczynowski, Bob Argiropoulos, Aly Karsan, Christian Buske, Mojca Jongen-Lavrencic, Michael Heuser, Tiziana Plati, R. Keith Humphries, Hartmut Döhner, Bernhard Gentner, Nicole Pochert, Tobias Berg, Florian Kuchenbauer, Milijana mirkovic-Hosle, Su Ming Sun, Sarah M Mah, Donna E. Hogge, Luigi Naldini, Fernando D. Camargo, Gentner, B, Pochert, N, Rouhi, A, Boccalatte, F, Plati, T, Berg, T, Sun, Sm, Mah, Sm, Mirkovic Hösle, M, Ruschmann, J, Muranyi, A, Leierseder, S, Argiropoulos, B, Starczynowski, Dt, Karsan, A, Heuser, M, Hogge, D, Camargo, Fd, Engelhardt, S, Döhner, H, Buske, C, Jongen Lavrencic, M, Naldini, Luigi, Humphries, Rk, Kuchenbauer, F., and Hematology
- Subjects
Adult ,Male ,Cancer Research ,Myeloid ,CD34 ,Mice, SCID ,Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,mir-223 ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Genetics ,medicine ,Animals ,Humans ,Erythropoiesis ,Lymphopoiesis ,RNA, Neoplasm ,Progenitor cell ,Molecular Biology ,030304 developmental biology ,Cell Proliferation ,Mice, Knockout ,0303 health sciences ,Myeloid leukemia ,Cell Biology ,Hematology ,Neoplasms, Experimental ,Middle Aged ,medicine.disease ,Fetal Blood ,Hematopoietic Stem Cells ,3. Good health ,Leukemia ,Haematopoiesis ,Leukemia, Myeloid, Acute ,MicroRNAs ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Neoplastic Stem Cells ,Female - Abstract
A precise understanding of the role of miR-223 in human hematopoiesis and in the pathogenesis of acute myeloid leukemia (AML) is still lacking. By measuring miR-223 expression in blasts from 115 AML patients, we found significantly higher miR-223 levels in patients with favorable prognosis, whereas patients with low miR-223 expression levels were associated with worse outcome. Furthermore, miR-223 was hierarchically expressed in AML subpopulations, with lower expression in leukemic stem cell–containing fractions. Genetic depletion of miR-223 decreased the leukemia initiating cell (LIC) frequency in a myelomonocytic AML mouse model, but it was not mandatory for rapid-onset AML. To relate these observations to physiologic myeloid differentiation, we knocked down or ectopically expressed miR-223 in cord-blood CD34 + cells using lentiviral vectors. Although miR-223 knockdown delayed myeloerythroid precursor differentiation in vitro, it increased myeloid progenitors in vivo following serial xenotransplantation. Ectopic miR-223 expression increased erythropoiesis, T lymphopoiesis, and early B lymphopoiesis in vivo. These findings broaden the role of miR-223 as a regulator of the expansion/differentiation equilibrium in hematopoietic stem and progenitor cells where its impact is dose- and differentiation-stage-dependent. This also explains the complex yet minor role of miR-223 in AML, a heterogeneous disease with variable degree of myeloid differentiation.
- Published
- 2015
36. Outcomes with allogeneic stem cell transplant using cryopreserved versus fresh hematopoietic progenitor cell products.
- Author
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Wan BA, Lindo L, Mourad YA, Chung S, Forrest D, Kuchenbauer F, Nantel S, Narayanan S, Nevill T, Power M, Rodrigo J, Sanford D, Song K, Stubbins RJ, Sutherland H, Toze CL, White J, Roy C, and Hay KA
- Subjects
- Humans, Male, Female, Middle Aged, Retrospective Studies, Adult, Graft vs Host Disease, Aged, SARS-CoV-2, Treatment Outcome, Hematologic Neoplasms therapy, Hematologic Neoplasms mortality, Cryopreservation methods, Hematopoietic Stem Cell Transplantation methods, COVID-19 therapy, Transplantation, Homologous methods, Hematopoietic Stem Cells
- Abstract
Background: Allogeneic hematopoietic stem cell transplant (alloHSCT) is a mainstay of treatment for hematologic malignancies such as acute leukemias and aggressive lymphomas. Historically, fresh hematopoietic progenitor cell (HPC) products have been preferred to cryopreserved products (cryo-HPC) due to concerns of loss of stem cell viability and number with the cryopreservation procedure., Objective: We aimed to analyze the outcomes of patients who received cryo-HPCs during the COVID-19 pandemic and compare this against historical cohorts that received fresh HPC., Study Design: A retrospective chart review was conducted on all adult patients who received a peripheral blood alloHSCT in British Columbia, Canada between June 2017 and November 2021. Baseline characteristics, Kaplan-Meier (KM) overall survival (OS), engraftment, and incidences of acute and chronic graft versus host disease were compared between patients who received cryo-HPCs and fresh HPCs. Univariable analysis followed by multivariable analysis was performed using a backward stepwise selection procedure to generate predictors of OS, cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and primary and secondary graft failure., Results: Three hundred eighty-three patients were included in the analysis, with cryo-HPC representing 40%. Median viability was higher in the fresh-HPC group at 99.2% (IQR 98.3-99.5) versus cryo-HPCs at 97.0% (96.0, 98.6) (P < 0.01). The 12-month actuarial survivals were 77% in the fresh HPC and 75% in the cryo-HPC groups (P = 0.21). There were no differences between cryo-HPCs and fresh HPCs on univariable analysis of OS, CIR, or NRM. There was a shorter median time to platelet engraftment in patients receiving fresh HPC at 17 days (IQR 16, 20) versus cryo-HPC at 21 days (IQR 18, 29), P < 0.001. There was a shorter median time to neutrophil engraftment in the fresh HPC group at 17 days (IQR 14, 20) versus 20 days (17, 23), P < 0.001. Cryo-HPC accounted for 5 out of 6 cases of primary graft failure (P = 0.04), and 3 out of five cases of secondary graft failure (P = 0.39). There were no significant differences in acute GVHD between the fresh HPC and cryo-HPC groups (P = 0.34). The incidence of moderate or severe chronic GVHD was 32% in the fresh-HPC group and 17% in the cryo-HPC group (P < 0.001). In multivariable analysis, cryopreservation did not emerge as an independent predictor of OS, CIR, NRM, primary GF or secondary GF. However, viability <90% on arrival at our center was a significant predictor of OS (HR 5.3, 2.3-12.3, P < 0.01), primary graft failure (OR 36.3, 5.4-210.2, P < 0.01), and secondary graft failure (OR 18.4, 1.7-121.1, P < 0.01)., Conclusions: Patients who received cryo-HPCs had similar OS and relapse rates to those who received fresh-HPCs but typically took 2-3 days longer to achieve engraftment of platelets or neutrophils and were associated increased primary graft failure. However, after accounting for multiple variables, cryopreservation was no longer a significant predictor of survival or engraftment while viability <90% emerged as an important predictor of OS, primary graft failure, and secondary graft failure. If confirmed, this suggests that viability on arrival at the infusion center may be a good quality control indicator used to identify HPC products that may warrant recollection if the risk of graft failure is sufficiently increased., Competing Interests: Declaration of Competing Interest The following authors have financial disclosures as outlined in the following: David Sanford, Membership on an entity's Board of Directors or advisory committees (Abbvie, Astellas); Kevin Song, honoraria (Janssen, Sanofi, BMS, Forus, Amgen, GSK, Gilead, Novartis); Shanee Chung, Consultancy & honoraria (Takeda), Honoraria (Astella Pharma, Novartis, Paladin, Pfizer); Ryan Stubbins, Honoraria (AbbVie, Pfizer, Jazz, Takeda), Advisory board (AbbVie), Research funding (Jazz); Heather Sutherland, Honoraria (Amgen, Forus, BMS); Kevin Hay, research funding (Janssen), Honoraria (BMS, Kite/Gilead, Novartis). The remaining authors have no competing interests or financial disclosures., (Copyright © 2024 International Society for Cell & Gene Therapy. All rights reserved.)
- Published
- 2024
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37. Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.
- Author
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Ghashghaei M, Liu Y, Ettles J, Bombaci G, Ramkumar N, Liu Z, Escano L, Miko SS, Kim Y, Waldron JA, Do K, MacPherson K, Yuen KA, Taibi T, Yue M, Arsalan A, Jin Z, Edin G, Karsan A, Morin GB, Kuchenbauer F, Perna F, Bushell M, and Vu LP
- Subjects
- Humans, Carcinogenesis genetics, Cell Differentiation, Receptors, CCR4, Leukemia, Myeloid, Acute genetics, Proteomics, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML., (© 2024. The Author(s).)
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- 2024
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38. Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy.
- Author
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Sharma M, Fu MP, Lu HY, Sharma AA, Modi BP, Michalski C, Lin S, Dalmann J, Salman A, Del Bel KL, Waqas M, Terry J, Setiadi A, Lavoie PM, Wasserman WW, Mwenifumbo J, Kobor MS, Lee AF, Kuchenbauer F, Lehman A, Cheng S, Cooper A, Patel MS, and Turvey SE
- Subjects
- Humans, Calcineurin genetics, Neoplasm Recurrence, Local, NFATC Transcription Factors genetics, NFATC Transcription Factors metabolism, Lymphoma, B-Cell genetics, Lymphoma, B-Cell metabolism, Contracture, Leukemia, B-Cell genetics, Leukemia, B-Cell metabolism, Osteochondroma
- Abstract
The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors., (© 2022 by The American Society of Hematology.)
- Published
- 2022
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39. Management of Acute Myeloid Leukemia: A Review for General Practitioners in Oncology.
- Author
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Stubbins RJ, Francis A, Kuchenbauer F, and Sanford D
- Subjects
- Aged, Azacitidine, Humans, General Practitioners, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy
- Abstract
Acute myeloid leukemia (AML) is a hematologic malignancy that most frequently develops in older adults. Overall, AML is associated with a high mortality although advancements in genetic risk stratification and new treatments are leading to improvements in outcomes for some subgroups. In this review, we discuss an individualized approach to intensive therapy with a focus on the role of recently approved novel therapies as well as the selection of post-remission therapies for patients in first remission. We discuss the management of patients with relapsed and refractory AML, including the role of targeted treatment and allogeneic stem cell transplant. Next, we review non-intensive treatment for older and unfit AML patients including the use of azacitidine and venetoclax. Finally, we discuss the integration of palliative care in the management of patients with AML.
- Published
- 2022
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40. The retinoic acid receptor co-factor NRIP1 is uniquely upregulated and represents a therapeutic target in acute myeloid leukemia with chromosome 3q rearrangements.
- Author
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Grasedieck S, Cabantog A, MacPhee L, Im J, Ruess C, Demir B, Sperb N, Rücker FG, Döhner K, Herold T, Pollack JR, Bullinger L, Rouhi A, and Kuchenbauer F
- Subjects
- Chromosome Aberrations, Chromosomes metabolism, Humans, MDS1 and EVI1 Complex Locus Protein genetics, Receptors, Retinoic Acid genetics, Leukemia, Myeloid, Acute pathology, Nuclear Receptor Interacting Protein 1 genetics, Nuclear Receptor Interacting Protein 1 metabolism
- Abstract
Aberrant expression of Ecotropic Viral Integration Site 1 (EVI1) is a hallmark of acute myeloid leukemia (AML) with inv(3) or t(3;3), which is a disease subtype with especially poor outcome. In studying transcriptomes from AML patients with chromosome 3q rearrangements, we identified a significant upregulation of the Nuclear Receptor Interacting Protein 1 (NRIP1) as well as its adjacent non-coding RNA LOC101927745. Utilizing transcriptomic and epigenomic data from over 900 primary samples from patients as well as genetic and transcriptional engineering approaches, we have identified several mechanisms that can lead to upregulation of NRIP1 in AML. We hypothesize that the LOC101927745 transcription start site harbors a context-dependent enhancer that is bound by EVI1, causing upregulation of NRIP1 in AML with chromosome 3 abnormalities. Furthermore, we showed that NRIP1 knockdown negatively affects the proliferation and survival of 3qrearranged AML cells and increases their sensitivity to all-trans retinoic acid, suggesting that NRIP1 is relevant for the pathogenesis of inv(3)/t(3;3) AML and could serve as a novel therapeutic target in myeloid malignancies with 3q abnormalities.
- Published
- 2022
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41. Maintenance With Hypomethylating Agents After Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis.
- Author
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Kungwankiattichai S, Ponvilawan B, Roy C, Tunsing P, Kuchenbauer F, and Owattanapanich W
- Abstract
Introduction: Hypomethylating agents (HMAs) seem to have a range of properties favorable to post-allogeneic hematopoietic stem cell transplantation (allo-SCT) maintenance in acute myeloid leukemia (AML) patients., Materials and Methods: The Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases were independently searched by two investigators to identify relevant studies published inception to 18 November 2021. These trials compared HMA maintenance to observation following allo-SCT for AML or myelodysplastic syndrome., Results: The meta-analysis eligibility criteria were fulfilled by 14 studies. The overall survival and relapse-free survival of the HMA maintenance group were superior to the observation group, with a pooled risk ratio (RR) of 1.38 and 1.46, respectively. Moreover, the cumulative incidence of relapse was significantly lower in those who received HMAs. The HMA group also had lower non-relapse mortality compared with the observation group. Overall, the incidences of grades III-IV acute graft-vs.-host disease (GVHD) and chronic GVHD did not differ in both groups. However, when looking specifically at those receiving decitabine maintenance, the rate of chronic GVHD seemed to be lower compared with observation alone., Conclusions: The current systematic review and meta-analysis illustrated that AML and MDS patients receiving HMA maintenance after allo-SCT had better outcomes in regards to OS, RFS, NRM, CIR as well as a reduced incidence of chronic GVHD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kungwankiattichai, Ponvilawan, Roy, Tunsing, Kuchenbauer and Owattanapanich.)
- Published
- 2022
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42. Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia.
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Niu X, Rothe K, Chen M, Grasedieck S, Li R, Nam SE, Zhang X, Novakovskiy GE, Ahn YH, Maksakova I, Lai S, Zhang H, Yan J, Liu H, Zhao Y, Wu D, Ge Y, Wasserman WW, Rouhi A, Kuchenbauer F, Yip CK, Zhang Z, and Jiang X
- Subjects
- Animals, Cell Line, Tumor, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Drug Delivery Systems, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute genetics, Neoplastic Stem Cells enzymology, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism, Sulfonamides pharmacology
- Abstract
The abundance of genetic abnormalities and phenotypic heterogeneities in acute myeloid leukemia (AML) poses significant challenges to the development of improved treatments. Here, we demonstrated that a key growth arrest-specific gene 6/AXL axis is highly activated in cells from patients with AML, particularly in stem/progenitor cells. We developed a potent selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition, alone or in combination with venetoclax, potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells and shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have a direct translational impact on the treatment of AML and other cancers with high AXL activity., (© 2021 by The American Society of Hematology.)
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- 2021
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43. A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma.
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Diesinger T, Lautwein A, Bergler S, Buckert D, Renz C, Dvorsky R, Buko V, Kirko S, Schneider E, Kuchenbauer F, Kumar M, Günes C, Genze F, Büchele B, Simmet T, Haslbeck M, Masur K, Barth T, Müller-Enoch D, Wirth T, and Haehner T
- Subjects
- Animals, Cytochrome P-450 CYP2E1 metabolism, Dodecanol, Humans, Mice, Mice, Nude, Oxidative Stress, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy
- Abstract
Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μ M. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Torsten Diesinger et al.)
- Published
- 2021
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44. The long non-coding RNA Cancer Susceptibility 15 ( CASC15 ) is induced by isocitrate dehydrogenase (IDH) mutations and maintains an immature phenotype in adult acute myeloid leukemia.
- Author
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Grasedieck S, Ruess C, Krowiorz K, Lux S, Pochert N, Schwarzer A, Klusmann JH, Jongen-Lavrencic M, Herold T, Bullinger L, Pollack JR, Rouhi A, and Kuchenbauer F
- Subjects
- Adult, Humans, Isocitrate Dehydrogenase genetics, Mutation, Phenotype, Leukemia, Myeloid, Acute genetics, RNA, Long Noncoding
- Published
- 2020
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- View/download PDF
45. Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis.
- Author
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Diesinger T, Buko V, Lautwein A, Dvorsky R, Belonovskaya E, Lukivskaya O, Naruta E, Kirko S, Andreev V, Buckert D, Bergler S, Renz C, Schneider E, Kuchenbauer F, Kumar M, Günes C, Büchele B, Simmet T, Müller-Enoch D, Wirth T, and Haehner T
- Subjects
- Alkanes chemical synthesis, Alkanes pharmacology, Alkanes therapeutic use, Animals, Cytochrome P-450 CYP2E1 chemistry, Cytochrome P-450 CYP2E1 Inhibitors chemical synthesis, Cytochrome P-450 CYP2E1 Inhibitors pharmacology, Fatty Liver, Alcoholic metabolism, Fatty Liver, Alcoholic pathology, Female, Hep G2 Cells, Humans, Lipoproteins, VLDL blood, Liver drug effects, Liver metabolism, Liver pathology, Oxidative Stress drug effects, Rats, Rats, Wistar, Reactive Oxygen Species metabolism, Severity of Illness Index, Triglycerides blood, Ursodeoxycholic Acid analysis, Cytochrome P-450 CYP2E1 metabolism, Cytochrome P-450 CYP2E1 Inhibitors therapeutic use, Fatty Liver, Alcoholic drug therapy
- Abstract
Background and Aims: Alcoholic steatohepatitis (ASH)-the inflammation of fatty liver-is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation-the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH., Methods: In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies., Results: A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol., Conclusions: Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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46. Meningioma 1 is indispensable for mixed lineage leukemia-rearranged acute myeloid leukemia.
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Sharma A, Jyotsana N, Gabdoulline R, Heckl D, Kuchenbauer F, Slany RK, Ganser A, and Heuser M
- Subjects
- Animals, Hematopoietic Stem Cells, Humans, Mice, Leukemia, Myeloid, Acute genetics, Trans-Activators genetics, Tumor Suppressor Proteins genetics
- Abstract
Mixed lineage leukemia ( MLL/KMT2A ) rearrangements (MLL-r) are one of the most frequent chromosomal aberrations in acute myeloid leukemia. We evaluated the function of Meningioma 1 (MN1), a co-factor of HOXA9 and MEIS1, in human and murine MLL-rearranged leukemia by CRISPR-Cas9 mediated deletion of MN1. MN1 was required for in vivo leukemogenicity of MLL positive murine and human leukemia cells. Loss of MN1 inhibited cell cycle and proliferation, promoted apoptosis and induced differentiation of MLL-rearranged cells. Expression analysis and chromatin immunoprecipitation with sequencing from previously reported data sets demonstrated that MN1 primarily maintains active transcription of HOXA9 and HOXA10, which are critical downstream genes of MLL, and their target genes like BCL2, MCL1 and Survivin. Treatment of MLL-rearranged primary leukemia cells with anti-MN1 siRNA significantly reduced their clonogenic potential in contrast to normal CD34
+ hematopoietic progenitor cells, suggesting a therapeutic window for MN1 targeting. In summary, our findings demonstrate that MN1 plays an essential role in MLL fusion leukemias and serve as a therapeutic target in MLL-rearranged acute myeloid leukemia., (Copyright© 2020 Ferrata Storti Foundation.)- Published
- 2020
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47. FLAMSA-RIC for Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis.
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Owattanapanich W, Ungprasert P, Wais V, Kungwankiattichai S, Bunjes D, and Kuchenbauer F
- Abstract
Reduced-intensity conditioning (RIC) regimens are established options for hematopoietic stem cell transplantation (HSCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the efficacy of RIC regimens for patients with high-risk disease is limited. The addition of a fludarabine, amsacrine, and cytarabine (FLAMSA)-sequential conditioning regimen was introduced for patients with high-risk MDS and AML to combine a high anti-leukemic activity with the advantages of RIC. The current systematic literature review and meta-analysis was conducted with the aim of identifying all cohort studies of patients with AML and/or MDS who received FLAMSA-RIC to determine its efficacy and toxicity. Out of 3044 retrieved articles, 12 published studies with 2395 overall patients (18.1-76.0 years; 96.8% AML and 3.2% MDS; follow-up duration of 0.7-145 months; 50.3% had active AML disease before HSCT) met the eligibility criteria and were included in the meta-analysis. In the pooled analysis, the 1- and 3-year overall survival (OS) rates were 59.6% (95% confidence interval (CI), 47.9-70.2%) and 40.2% (95% CI, 28.0-53.7%), respectively. The pooled 3-year OS rate of the patients who achieved CR1 or CR2 prior to HSCT was 60.1% (95% CI, 55.1-64.8%) and the percentage of those with relapse or refractory disease was 27.8% (95% CI, 23.3-32.8%). The pooled 3-year leukemia-free survival (LFS) rate was 39.3% (95% CI, 26.4-53.9%). Approximately 29% of the patients suffered from grades 2-4 acute graft-versus-host disease (GVHD), while 35.6% had chronic GVHD. The pooled 1- and 3-year non-relapse mortality (NRM) rates were 17.9% (95% CI, 16.1-19.8%) and 21.1% (95% CI, 18.8-23.7%), respectively. Our data indicates that the FLAMSA-RIC regimen is an effective and well-tolerated regimen for HSCT in patients with high-risk AML and MDS.
- Published
- 2019
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48. Pulmonary Campylobacter concisus infection in an immunocompromised patient with underlying mucormycosis.
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Hagemann JB, Haverkamp S, Grüner B, Kuchenbauer F, and Essig A
- Subjects
- Anti-Bacterial Agents pharmacology, Drug Resistance, Multiple, Bacterial, Hematopoietic Stem Cell Transplantation, Humans, Immunocompromised Host, Lung Abscess diagnosis, Lung Abscess microbiology, Macrolides pharmacology, Male, Quinolones pharmacology, Respiratory Tract Infections diagnosis, beta-Lactams pharmacology, Campylobacter isolation & purification, Campylobacter Infections diagnosis, Mucormycosis diagnosis, Respiratory Tract Infections microbiology
- Abstract
Campylobacter concisus is a rarely encountered agent of human infection. The first isolation of C. concisus from a pulmonary abscess in an immunocompromised patient who underwent allogeneic stem cell transplantation is reported here. This unusual case demonstrates the pathogenic potential of this bacterium and outlines species-immanent difficulties in gaining a reliable diagnosis. Molecular methods were a cornerstone for definite identification of the organism grown on anaerobic culture from surgically excised tissue. Antimicrobial susceptibility testing revealed unusual quinolone and macrolide resistance, and therefore antimicrobial therapy was based on β-lactam antibiotics., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2018
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49. Revisiting thrombocytopenia in acute promyelocytic leukemia.
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Kuchenbauer F and Buske C
- Subjects
- Humans, Leukemia, Promyelocytic, Acute blood, Leukemia, Promyelocytic, Acute drug therapy, Membrane Glycoproteins physiology, Platelet Aggregation, Tretinoin therapeutic use, Leukemia, Promyelocytic, Acute complications, Thrombocytopenia etiology
- Published
- 2018
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50. The Differential Diagnosis and Treatment of Thrombotic Microangiopathies.
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Bommer M, Wölfle-Guter M, Bohl S, and Kuchenbauer F
- Subjects
- ADAMTS13 Protein analysis, ADAMTS13 Protein blood, Diagnosis, Differential, Hematology methods, Hemolytic-Uremic Syndrome diagnosis, Humans, Purpura, Thrombotic Thrombocytopenic diagnosis, Thrombotic Microangiopathies classification, Thrombotic Microangiopathies diagnosis
- Abstract
Background: Thrombotic microangiopathies are rare, life-threatening diseaseswhose care involves physicians from multiple specialties. The past five years haveseen major advances in our understanding of the pathophysiology, classification,and treatment of these conditions. Their timely diagnosis and prompt treatment cansave lives., Methods: This review is based on pertinent articles published up to 17 December2017 that were retrieved by a selective search of the National Library of Medicine'sPubMed database employing the terms "thrombotic microangiopathy," "thromboticthrombocytopenic purpura," "hemolytic-uremic syndrome," "drug-induced TMA," and"EHEC-HUS.", Results: The classic types of thrombotic microangiopathy are thrombotic thrombo -cytopenic purpura (TTP) and typical hemolytic-uremic syndrome (HUS), also knownas enterohemorrhagic Escherichia coli-associated HUS (EHEC-HUS). There are anumber of further types from which these must be differentiated. The key test,beyond a basic hematological evaluation including a peripheral blood smear, ismeasurement of the blood level of the protease that splits von Willebrand factor,which is designated ADAMTS13 (a disintegrin and metalloprotease with thrombo -spondin type 1 motif, member 13). The quantitative determination of ADAMTS13, ofADAMTS13 activity, and of the ADAMTS13 inhibitor serves to differentiate TTP fromother types of thrombotic microangiopathy. As TTP requires urgent treatment,plasmapheresis should be begun as soon as TTP is suspected on the basis of afinding of hemolysis with schistocytes and thrombocytopenia. The treatment shouldbe altered as indicated once the laboratory findings become available., Conclusion: Rapid differential diagnosis is needed in order to determine the specifictype of thrombotic microangiopathy that is present, because only patients with TTPand only a very small percentage of those with atypical hemolytic-uremic syndrome(aHUS) can benefit from plasmapheresis. The establishment of a nationwideregistry in Germany with an attached biobank might help reveal yet unknowngenetic predispositions.
- Published
- 2018
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