Mathew, Nimitha R. and Baumgartner, Francis and Braun, Lukas and O'Sullivan, David and Thomas, Simone and Waterhouse, Miguel and Mueller, Tony A. and Hanke, Kathrin and Taromi, Sanaz and Apostolova, Petya and Illert, Anna L. and Melchinger, Wolfgang and Duquesne, Sandra and Schmitt-Graeff, Annette and Osswald, Lena and Yan, Kai-Li and Weber, Arnim and Tugues, Sonia and Spath, Sabine and Pfeifer, Dietmar and Follo, Marie and Claus, Rainer and Luebbert, Michael and Rummelt, Christoph and Bertz, Hartmut and Waesch, Ralph and Haag, Johanna and Schmidts, Andrea and Schultheiss, Michael and Bettinger, Dominik and Thimme, Robert and Ullrich, Evelyn and Tanriver, Yakup and Vuong, Giang Lam and Arnold, Renate and Hemmati, Philipp and Wolf, Dominik and Ditschkowski, Markus and Jilg, Cordula and Wilhelm, Konrad and Leiber, Christian and Gerull, Sabine and Halter, Joerg and Lengerke, Claudia and Pabst, Thomas and Schroeder, Thomas and Kobbe, Guido and Roesler, Wolf and Doostkam, Soroush and Meckel, Stephan and Stabla, Kathleen and Metzelder, Stephan K. and Halbach, Sebastian and Brummer, Tilman and Hu, Zehan and Dengjel, Joern and Hackanson, Bjoern and Schmid, Christoph and Holtick, Udo and Scheid, Christof and Spyridonidis, Alexandros and Stoelzel, Friedrich and Ordemann, Rainer and Mueller, Lutz P. and Sicre-de-Fontbrune, Flore and Ihorst, Gabriele and Kuball, Juergen and Ehlert, Jan E. and Feger, Daniel and Wagner, Eva-Maria and Cahn, Jean-Yves and Schnell, Jacqueline and Kuchenbauer, Florian and Bunjes, Donald and Chakraverty, Ronjon and Richardson, Simon and Gill, Saar and Kroeger, Nicolaus and Ayuk, Francis and Vago, Luca and Ciceri, Fabio and Mueller, Antonia M. and Kondo, Takeshi and Teshima, Takanori and Klaeger, Susan and Kuster, Bernhard and Kim, Dennis (Dong Hwan) and Weisdorf, Daniel and van der Velden, Walter and Doerfel, Daniela and Bethge, Wolfgang and Hilgendorf, Inken and Hochhaus, Andreas and Andrieux, Geoffroy and Boerries, Melanie and Busch, Hauke and Magenau, John and Reddy, Pavan and Labopin, Myriam and Antin, Joseph H. and Henden, Andrea S. and Hill, Geoffrey R. and Kennedy, Glen A. and Bar, Merav and Sarma, Anita and McLornan, Donal and Mufti, Ghulam and Oran, Betul and Rezvani, Katayoun and Shah, Omid and Negrin, Robert S. and Nagler, Arnon and Prinz, Marco and Burchert, Andreas and Neubauer, Andreas and Beelen, Dietrich and Mackensen, Andreas and von Bubnoff, Nikolas and Herr, Wolfgang and Becher, Burkhard and Socie, Gerard and Caligiuri, Michael A. and Ruggiero, Eliana and Bonini, Chiara and Haecker, Georg and Duyster, Justus and Finke, Juergen and Pearce, Erika and Blazar, Bruce R. and Zeiser, Robert (2018) Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. NATURE MEDICINE, 24 (3). 282-+. ISSN 1078-8956, 1546-170X
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; HOST-DISEASE; REGULATORY FACTOR; ACUTE GVHD; ALLO-SCT; TRANSPLANTATION; INTERLEUKIN-15; ACTIVATION; MAINTENANCE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Mar 2020 12:58 |
| Last Modified: | 16 Mar 2020 12:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14989 |
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