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Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Standard

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. / Mathew, Nimitha R; Baumgartner, Francis; Braun, Lukas; O'Sullivan, David; Thomas, Simone; 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.

in: NAT MED, Jahrgang 24, Nr. 3, 03.2018, S. 282-291.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Mathew, NR, Baumgartner, F, Braun, L, O'Sullivan, D, Thomas, S, Waterhouse, M, Müller, TA, Hanke, K, Taromi, S, Apostolova, P, Illert, AL, Melchinger, W, Duquesne, S, Schmitt-Graeff, A, Osswald, L, Yan, K-L, Weber, A, Tugues, S, Spath, S, Pfeifer, D, Follo, M, Claus, R, Lübbert, M, Rummelt, C, Bertz, H, Wäsch, R, Haag, J, Schmidts, A, Schultheiss, M, Bettinger, D, Thimme, R, Ullrich, E, Tanriver, Y, Vuong, GL, 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, Rösler, W, Doostkam, S, Meckel, S, Stabla, K, Metzelder, SK, Halbach, S, Brummer, T, Hu, Z, Dengjel, J, Hackanson, B, Schmid, C, Holtick, U, Scheid, C, Spyridonidis, A, Stölzel, F, Ordemann, R, Müller, LP, Sicre-de-Fontbrune, F, Ihorst, G, Kuball, J, Ehlert, JE, Feger, D, Wagner, E-M, Cahn, J-Y, Schnell, J, Kuchenbauer, F, Bunjes, D, Chakraverty, R, Richardson, S, Gill, S, Kröger, N, Ayuk, F, Vago, L, Ciceri, F, Müller, AM, Kondo, T, Teshima, T, Klaeger, S, Kuster, B, Kim, DDH, Weisdorf, D, van der Velden, W, Dörfel, D, Bethge, W, Hilgendorf, I, Hochhaus, A, Andrieux, G, Börries, M, Busch, H, Magenau, J, Reddy, P, Labopin, M, Antin, JH, Henden, AS, Hill, GR, Kennedy, GA, Bar, M, Sarma, A, McLornan, D, Mufti, G, Oran, B, Rezvani, K, Shah, O, Negrin, RS, Nagler, A, Prinz, M, Burchert, A, Neubauer, A, Beelen, D, Mackensen, A, von Bubnoff, N, Herr, W, Becher, B, Socié, G, Caligiuri, MA, Ruggiero, E, Bonini, C, Häcker, G, Duyster, J, Finke, J, Pearce, E, Blazar, BR & Zeiser, R 2018, 'Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells', NAT MED, Jg. 24, Nr. 3, S. 282-291. https://doi.org/10.1038/nm.4484

APA

Mathew, N. R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Müller, 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., ... Zeiser, R. (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), 282-291. https://doi.org/10.1038/nm.4484

Vancouver

Mathew NR, Baumgartner F, Braun L, O'Sullivan D, Thomas S, Waterhouse M et al. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. NAT MED. 2018 Mär;24(3):282-291. https://doi.org/10.1038/nm.4484

Bibtex

@article{33d2312835d24ccdafe3a159c012ce3d,
title = "Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells",
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-γ+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.",
keywords = "Journal Article",
author = "Mathew, {Nimitha R} and Francis Baumgartner and Lukas Braun and David O'Sullivan and Simone Thomas and Miguel Waterhouse and M{\"u}ller, {Tony A} and Kathrin Hanke and Sanaz Taromi and Petya Apostolova and Illert, {Anna L} and Wolfgang Melchinger and Sandra Duquesne and Annette Schmitt-Graeff and Lena Osswald and Kai-Li Yan and Arnim Weber and Sonia Tugues and Sabine Spath and Dietmar Pfeifer and Marie Follo and Rainer Claus and Michael L{\"u}bbert and Christoph Rummelt and Hartmut Bertz and Ralph W{\"a}sch and Johanna Haag and Andrea Schmidts and Michael Schultheiss and Dominik Bettinger and Robert Thimme and Evelyn Ullrich and Yakup Tanriver and Vuong, {Giang Lam} and Renate Arnold and Philipp Hemmati and Dominik Wolf and Markus Ditschkowski and Cordula Jilg and Konrad Wilhelm and Christian Leiber and Sabine Gerull and J{\"o}rg Halter and Claudia Lengerke and Thomas Pabst and Thomas Schroeder and Guido Kobbe and Wolf R{\"o}sler and Soroush Doostkam and Stephan Meckel and Kathleen Stabla and Metzelder, {Stephan K} and Sebastian Halbach and Tilman Brummer and Zehan Hu and Joern Dengjel and Bj{\"o}rn Hackanson and Christoph Schmid and Udo Holtick and Christof Scheid and Alexandros Spyridonidis and Friedrich St{\"o}lzel and Rainer Ordemann and M{\"u}ller, {Lutz P} and Flore Sicre-de-Fontbrune and Gabriele Ihorst and J{\"u}rgen Kuball and Ehlert, {Jan E} and Daniel Feger and Eva-Maria Wagner and Jean-Yves Cahn and Jacqueline Schnell and Florian Kuchenbauer and Donald Bunjes and Ronjon Chakraverty and Simon Richardson and Saar Gill and Nicolaus Kr{\"o}ger and Francis Ayuk and Luca Vago and Fabio Ciceri and M{\"u}ller, {Antonia M} and Takeshi Kondo and Takanori Teshima and Susan Klaeger and Bernhard Kuster and Kim, {Dennis Dong Hwan} and Daniel Weisdorf and {van der Velden}, Walter and Daniela D{\"o}rfel and Wolfgang Bethge and Inken Hilgendorf and Andreas Hochhaus and Geoffroy Andrieux and Melanie B{\"o}rries and Hauke Busch and John Magenau and Pavan Reddy and Myriam Labopin and Antin, {Joseph H} and Henden, {Andrea S} and Hill, {Geoffrey R} and Kennedy, {Glen A} and Merav Bar and Anita Sarma and Donal McLornan and Ghulam Mufti and Betul Oran and Katayoun Rezvani and Omid Shah and Negrin, {Robert S} and Arnon Nagler and Marco Prinz and Andreas Burchert and Andreas Neubauer and Dietrich Beelen and Andreas Mackensen and {von Bubnoff}, Nikolas and Wolfgang Herr and Burkhard Becher and Gerard Soci{\'e} and Caligiuri, {Michael A} and Eliana Ruggiero and Chiara Bonini and Georg H{\"a}cker and Justus Duyster and J{\"u}rgen Finke and Erika Pearce and Blazar, {Bruce R} and Robert Zeiser",
year = "2018",
month = mar,
doi = "10.1038/nm.4484",
language = "English",
volume = "24",
pages = "282--291",
journal = "NAT MED",
issn = "1078-8956",
publisher = "NATURE PUBLISHING GROUP",
number = "3",

}

RIS

TY - JOUR

T1 - Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

AU - Mathew, Nimitha R

AU - Baumgartner, Francis

AU - Braun, Lukas

AU - O'Sullivan, David

AU - Thomas, Simone

AU - Waterhouse, Miguel

AU - Müller, Tony A

AU - Hanke, Kathrin

AU - Taromi, Sanaz

AU - Apostolova, Petya

AU - Illert, Anna L

AU - Melchinger, Wolfgang

AU - Duquesne, Sandra

AU - Schmitt-Graeff, Annette

AU - Osswald, Lena

AU - Yan, Kai-Li

AU - Weber, Arnim

AU - Tugues, Sonia

AU - Spath, Sabine

AU - Pfeifer, Dietmar

AU - Follo, Marie

AU - Claus, Rainer

AU - Lübbert, Michael

AU - Rummelt, Christoph

AU - Bertz, Hartmut

AU - Wäsch, Ralph

AU - Haag, Johanna

AU - Schmidts, Andrea

AU - Schultheiss, Michael

AU - Bettinger, Dominik

AU - Thimme, Robert

AU - Ullrich, Evelyn

AU - Tanriver, Yakup

AU - Vuong, Giang Lam

AU - Arnold, Renate

AU - Hemmati, Philipp

AU - Wolf, Dominik

AU - Ditschkowski, Markus

AU - Jilg, Cordula

AU - Wilhelm, Konrad

AU - Leiber, Christian

AU - Gerull, Sabine

AU - Halter, Jörg

AU - Lengerke, Claudia

AU - Pabst, Thomas

AU - Schroeder, Thomas

AU - Kobbe, Guido

AU - Rösler, Wolf

AU - Doostkam, Soroush

AU - Meckel, Stephan

AU - Stabla, Kathleen

AU - Metzelder, Stephan K

AU - Halbach, Sebastian

AU - Brummer, Tilman

AU - Hu, Zehan

AU - Dengjel, Joern

AU - Hackanson, Björn

AU - Schmid, Christoph

AU - Holtick, Udo

AU - Scheid, Christof

AU - Spyridonidis, Alexandros

AU - Stölzel, Friedrich

AU - Ordemann, Rainer

AU - Müller, Lutz P

AU - Sicre-de-Fontbrune, Flore

AU - Ihorst, Gabriele

AU - Kuball, Jürgen

AU - Ehlert, Jan E

AU - Feger, Daniel

AU - Wagner, Eva-Maria

AU - Cahn, Jean-Yves

AU - Schnell, Jacqueline

AU - Kuchenbauer, Florian

AU - Bunjes, Donald

AU - Chakraverty, Ronjon

AU - Richardson, Simon

AU - Gill, Saar

AU - Kröger, Nicolaus

AU - Ayuk, Francis

AU - Vago, Luca

AU - Ciceri, Fabio

AU - Müller, Antonia M

AU - Kondo, Takeshi

AU - Teshima, Takanori

AU - Klaeger, Susan

AU - Kuster, Bernhard

AU - Kim, Dennis Dong Hwan

AU - Weisdorf, Daniel

AU - van der Velden, Walter

AU - Dörfel, Daniela

AU - Bethge, Wolfgang

AU - Hilgendorf, Inken

AU - Hochhaus, Andreas

AU - Andrieux, Geoffroy

AU - Börries, Melanie

AU - Busch, Hauke

AU - Magenau, John

AU - Reddy, Pavan

AU - Labopin, Myriam

AU - Antin, Joseph H

AU - Henden, Andrea S

AU - Hill, Geoffrey R

AU - Kennedy, Glen A

AU - Bar, Merav

AU - Sarma, Anita

AU - McLornan, Donal

AU - Mufti, Ghulam

AU - Oran, Betul

AU - Rezvani, Katayoun

AU - Shah, Omid

AU - Negrin, Robert S

AU - Nagler, Arnon

AU - Prinz, Marco

AU - Burchert, Andreas

AU - Neubauer, Andreas

AU - Beelen, Dietrich

AU - Mackensen, Andreas

AU - von Bubnoff, Nikolas

AU - Herr, Wolfgang

AU - Becher, Burkhard

AU - Socié, Gerard

AU - Caligiuri, Michael A

AU - Ruggiero, Eliana

AU - Bonini, Chiara

AU - Häcker, Georg

AU - Duyster, Justus

AU - Finke, Jürgen

AU - Pearce, Erika

AU - Blazar, Bruce R

AU - Zeiser, Robert

PY - 2018/3

Y1 - 2018/3

N2 - 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-γ+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.

AB - 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-γ+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.

KW - Journal Article

U2 - 10.1038/nm.4484

DO - 10.1038/nm.4484

M3 - SCORING: Journal article

C2 - 29431743

VL - 24

SP - 282

EP - 291

JO - NAT MED

JF - NAT MED

SN - 1078-8956

IS - 3

ER -