; Waterhouse, Miguel ; Müller, Tony A. ; Hanke, Kathrin ; Taromi, Sanaz ; Apostolova, Petya ; Illert, Anna L. ; Melchinger, Wolfgang ; Duquesne, Sandra ; Schmitt-Graeff, Annette ; Osswald, Lena ; Yan, Kai-Li ; Weber, Arnim ; Tugues, Sonia ; Spath, Sabine
; Pfeifer, Dietmar ; Follo, Marie ; Claus, Rainer ; Lübbert, Michael ; Rummelt, Christoph ; Bertz, Hartmut ; Wäsch, Ralph ; Haag, Johanna ; Schmidts, Andrea
; Schultheiss, Michael ; Bettinger, Dominik ; Thimme, Robert ; Ullrich, Evelyn
; Tanriver, Yakup
; Vuong, Giang Lam ; Arnold, Renate ; Hemmati, Philipp ; Wolf, Dominik ; Ditschkowski, Markus ; Jilg, Cordula ; Wilhelm, Konrad ; Leiber, Christian ; Gerull, Sabine ; Halter, Jörg ; Lengerke, Claudia
; Pabst, Thomas ; Schroeder, Thomas ; Kobbe, Guido ; Rösler, Wolf ; Doostkam, Soroush ; Meckel, Stephan
; Stabla, Kathleen ; Metzelder, Stephan K. ; Halbach, Sebastian
; Brummer, Tilman
; Hu, Zehan ; Dengjel, Joern
; Hackanson, Björn ; Schmid, Christoph ; Holtick, Udo ; Scheid, Christof ; Spyridonidis, Alexandros ; Stölzel, Friedrich ; Ordemann, Rainer ; Müller, Lutz P. ; Sicre-de-Fontbrune, Flore ; Ihorst, Gabriele ; Kuball, Jürgen ; Ehlert, Jan E. ; Feger, Daniel ; Wagner, Eva-Maria ; Cahn, Jean-Yves ; Schnell, Jacqueline ; Kuchenbauer, Florian ; Bunjes, Donald ; Chakraverty, Ronjon
; Richardson, Simon
; Gill, Saar ; Kröger, Nicolaus ; Ayuk, Francis ; Vago, Luca
; Ciceri, Fabio ; Müller, Antonia M. ; Kondo, Takeshi
; Teshima, Takanori ; Klaeger, Susan ; Kuster, Bernhard ; Kim, Dennis (Dong Hwan) ; Weisdorf, Daniel ; van der Velden, Walter ; Dörfel, Daniela ; Bethge, Wolfgang ; Hilgendorf, Inken ; Hochhaus, Andreas ; Andrieux, Geoffroy ; Börries, Melanie ; Busch, Hauke
; Magenau, John ; Reddy, Pavan ; Labopin, Myriam ; Antin, Joseph H. ; Henden, Andrea S.
; Hill, Geoffrey R. ; Kennedy, Glen A. ; Bar, Merav ; Sarma, Anita ; McLornan, Donal ; Mufti, Ghulam ; Oran, Betul ; Rezvani, Katayoun ; Shah, Omid ; Negrin, Robert S. ; Nagler, Arnon ; Prinz, Marco ; Burchert, Andreas ; Neubauer, Andreas ; Beelen, Dietrich ; Mackensen, Andreas ; von Bubnoff, Nikolas ; Herr, Wolfgang ; Becher, Burkhard ; Socié, Gerard ; Caligiuri, Michael A. ; Ruggiero, Eliana ; Bonini, Chiara ; Häcker, Georg ; Duyster, Justus ; Finke, Jürgen ; Pearce, Erika ; Blazar, Bruce R. ; Zeiser, Robert | Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | Nature Medicine | ||||
| Publisher: | Nature | ||||
| Place of Publication: | NEW YORK | ||||
| Volume: | 24 | ||||
| Number of Issue or Book Chapter: | 3 | ||||
| Page Range: | pp. 282-291 | ||||
| Date: | 2018 | ||||
| Institutions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) | ||||
| Identification Number: |
| ||||
| Keywords: | ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; HOST-DISEASE; REGULATORY FACTOR; ACUTE GVHD; ALLO-SCT; TRANSPLANTATION; INTERLEUKIN-15; ACTIVATION; MAINTENANCE; | ||||
| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
| Status: | Published | ||||
| Refereed: | Yes, this version has been refereed | ||||
| Created at the University of Regensburg: | Yes | ||||
| Item ID: | 47433 |
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 ...

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.
Metadata last modified: 27 Aug 2021 08:42
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