Mathew, Nimitha R., Baumgartner, Francis ORCID: 0000-0003-0768-1956, Braun, Lukas, O'Sullivan, David, Thomas, Simone ORCID: 0000-0001-6308-3649, Waterhouse, Miguel, Mueller, Tony A., Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya ORCID: 0000-0002-3856-5109, Illert, Anna L., Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine ORCID: 0000-0002-2689-1951, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer ORCID: 0000-0003-2617-8766, Luebbert, Michael, Rummelt, Christoph ORCID: 0000-0002-6471-7030, Bertz, Hartmut, Waesch, Ralph, Haag, Johanna, Schmidts, Andrea ORCID: 0000-0001-7035-1584, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn ORCID: 0000-0001-8530-1192, Tanriver, Yakup ORCID: 0000-0002-4806-2548, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Markus, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Joerg, Lengerke, Claudia ORCID: 0000-0001-5442-2805, Pabst, Thomas, Schroeder, Thomas, Kobbe, Guido, Roesler, Wolf, Doostkam, Soroush, Meckel, Stephan ORCID: 0000-0001-6468-4526, Stabla, Kathleen, Metzelder, Stephan K., Halbach, Sebastian ORCID: 0000-0002-6827-8178, Brummer, Tilman ORCID: 0000-0003-4387-7905, Hu, Zehan, Dengjel, Joern ORCID: 0000-0002-9453-4614, Hackanson, Bjoern, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandros, Stoelzel, Friedrich, Ordemann, Rainer, Mueller, Lutz P., Sicre-de-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Juergen, Ehlert, Jan E., Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yves, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon ORCID: 0000-0003-2301-2664, Richardson, Simon ORCID: 0000-0003-4343-4784, Gill, Saar, Kroeger, Nicolaus, Ayuk, Francis, Vago, Luca ORCID: 0000-0003-4247-3175, Ciceri, Fabio, Mueller, Antonia M., Kondo, Takeshi ORCID: 0000-0001-7455-5824, Teshima, Takanori, Klaeger, Susan ORCID: 0000-0002-0074-5163, Kuster, Bernhard, Kim, Dennis (Dong Hwan), Weisdorf, Daniel, van der Velden, Walter, Doerfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken ORCID: 0000-0003-2038-9730, Hochhaus, Andreas, Andrieux, Geoffroy, Boerries, Melanie, Busch, Hauke ORCID: 0000-0003-4763-4521, 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, Socie, Gerard, Caligiuri, Michael A., Ruggiero, Eliana ORCID: 0000-0002-2954-8278, Bonini, Chiara, Haecker, Georg, Duyster, Justus, Finke, Juergen, Pearce, Erika, 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. Nat. Med., 24 (3). S. 282 - 295. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-170X

Full text not available from this repository.

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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mathew, Nimitha R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumgartner, FrancisUNSPECIFIEDorcid.org/0000-0003-0768-1956UNSPECIFIED
Braun, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Sullivan, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, SimoneUNSPECIFIEDorcid.org/0000-0001-6308-3649UNSPECIFIED
Waterhouse, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Tony A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanke, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taromi, SanazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Apostolova, PetyaUNSPECIFIEDorcid.org/0000-0002-3856-5109UNSPECIFIED
Illert, Anna L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Melchinger, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duquesne, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt-Graeff, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osswald, LenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yan, Kai-LiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, ArnimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tugues, SoniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spath, SabineUNSPECIFIEDorcid.org/0000-0002-2689-1951UNSPECIFIED
Pfeifer, DietmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Follo, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claus, RainerUNSPECIFIEDorcid.org/0000-0003-2617-8766UNSPECIFIED
Luebbert, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rummelt, ChristophUNSPECIFIEDorcid.org/0000-0002-6471-7030UNSPECIFIED
Bertz, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waesch, RalphUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haag, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidts, AndreaUNSPECIFIEDorcid.org/0000-0001-7035-1584UNSPECIFIED
Schultheiss, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bettinger, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thimme, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, EvelynUNSPECIFIEDorcid.org/0000-0001-8530-1192UNSPECIFIED
Tanriver, YakupUNSPECIFIEDorcid.org/0000-0002-4806-2548UNSPECIFIED
Vuong, Giang LamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arnold, RenateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemmati, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ditschkowski, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jilg, CordulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilhelm, KonradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leiber, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerull, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halter, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lengerke, ClaudiaUNSPECIFIEDorcid.org/0000-0001-5442-2805UNSPECIFIED
Pabst, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeder, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kobbe, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roesler, WolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doostkam, SoroushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meckel, StephanUNSPECIFIEDorcid.org/0000-0001-6468-4526UNSPECIFIED
Stabla, KathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Metzelder, Stephan K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halbach, SebastianUNSPECIFIEDorcid.org/0000-0002-6827-8178UNSPECIFIED
Brummer, TilmanUNSPECIFIEDorcid.org/0000-0003-4387-7905UNSPECIFIED
Hu, ZehanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dengjel, JoernUNSPECIFIEDorcid.org/0000-0002-9453-4614UNSPECIFIED
Hackanson, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmid, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holtick, UdoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheid, ChristofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spyridonidis, AlexandrosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoelzel, FriedrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ordemann, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Lutz P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sicre-de-Fontbrune, FloreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihorst, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuball, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehlert, Jan E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feger, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, Eva-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cahn, Jean-YvesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnell, JacquelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuchenbauer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bunjes, DonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chakraverty, RonjonUNSPECIFIEDorcid.org/0000-0003-2301-2664UNSPECIFIED
Richardson, SimonUNSPECIFIEDorcid.org/0000-0003-4343-4784UNSPECIFIED
Gill, SaarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroeger, NicolausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ayuk, FrancisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vago, LucaUNSPECIFIEDorcid.org/0000-0003-4247-3175UNSPECIFIED
Ciceri, FabioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Antonia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kondo, TakeshiUNSPECIFIEDorcid.org/0000-0001-7455-5824UNSPECIFIED
Teshima, TakanoriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klaeger, SusanUNSPECIFIEDorcid.org/0000-0002-0074-5163UNSPECIFIED
Kuster, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Dennis (Dong Hwan)UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weisdorf, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Velden, WalterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doerfel, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bethge, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilgendorf, InkenUNSPECIFIEDorcid.org/0000-0003-2038-9730UNSPECIFIED
Hochhaus, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrieux, GeoffroyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boerries, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Busch, HaukeUNSPECIFIEDorcid.org/0000-0003-4763-4521UNSPECIFIED
Magenau, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reddy, PavanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Labopin, MyriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antin, Joseph H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henden, Andrea S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hill, Geoffrey R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kennedy, Glen A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bar, MeravUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarma, AnitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McLornan, DonalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mufti, GhulamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oran, BetulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rezvani, KatayounUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, OmidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Negrin, Robert S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nagler, ArnonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prinz, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burchert, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neubauer, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beelen, DietrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mackensen, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Bubnoff, NikolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herr, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becher, BurkhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Socie, GerardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caligiuri, Michael A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruggiero, ElianaUNSPECIFIEDorcid.org/0000-0002-2954-8278UNSPECIFIED
Bonini, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haecker, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duyster, JustusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finke, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pearce, ErikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blazar, Bruce R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeiser, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-194793
DOI: 10.1038/nm.4484
Journal or Publication Title: Nat. Med.
Volume: 24
Number: 3
Page Range: S. 282 - 295
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-170X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; HOST-DISEASE; REGULATORY FACTOR; ACUTE GVHD; ALLO-SCT; TRANSPLANTATION; INTERLEUKIN-15; ACTIVATION; MAINTENANCEMultiple languages
Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19479

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