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1. An improved molecular inversion probe based targeted sequencing approach for low variant allele frequency- Supplementary Tables

Author

Biezuner Tamir, Brilon Yardena, Asaf, Ben Arye, Barak, Oron, Kadam Aditee, Danin Adi, Furer Nili, Minden Mark D, Kim, Dennis Dong Hwan, Shapira Ahiran, Nadir, Arber, John, Dick, Thavendiranathan Paaladinesh, Moskovitz Yoni, Kaushansky Nathali, Chapal-Ilani Noa, and Shlush Liran, I.

Abstract

Deep targeted sequencing technologies are still not widely used in clinical practice due to the complexity of the methods and their cost. The Molecular Inversion Probes (MIP) technology is cost effective and scalable in the number of targets, however, suffers from low overall performance especially in GC rich regions. In order to improve the MIP performance, we sequenced a large cohort of healthy individuals (n=4417), with a panel of 616 MIPs, at high depth in duplicates. To improve the previous state-of-the-art statistical model for low variant allele frequency, we selected 4635 potentially positive variants and validated them using amplicon sequencing. Using machine learning prediction tools, we significantly improved precision of 10% to 56.25% (p0.005. We further developed biochemically modified MIP protocol and improved its turn-around-time to ~4 hours. Our new biochemistry significantly improved uniformity, GC-Rich regions coverage, and enabled 95% on target reads in a large MIP panel of 8349 genomic targets. Overall, we demonstrate an enhancement of the MIP targeted sequencing approach in both detection of low frequency variants and in other key parameters, paving its way to become an ultrafast cost-effective research and clinical diagnostic tool.

Published
2021
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2. High Overall and GVHD-Free Survival in Patients with Aplastic Anemia Receiving in vivo T-cell Depletion Transplants and Long-Term Complications

Author

Salas, Maria Queralt, Atenafu, Eshetu G., Lam, Wilson, Law, Arjun Datt, Kim, Dennis (Dong Hwan), Michelis, Fotios V., Al-Shaibani, Zeyad, Gerbitz, Armin, Lipton, Jeffrey Howard, Viswabandya, Auro, Mattsson, Jonas, Gupta, Vikas, and Kumar, Rajat

Subjects
Original Article, Industrial and Manufacturing Engineering
Abstract

We report a single-center experience of allogeneic hematopoietic stem cell transplant for patients with severe aplastic anemia over 13 years of age. Fifty-eight patients were included, and in vivo T-cell depletion was used in all cases. Fifty-one (88%) received alemtuzumab and 7 (12%) were given rabbit anti-thymocyte globulin. The median follow-up period was 6 years (range: 0-13.5). Data was collected retrospectively and updated in April 2019. The median age was 31 years (range: 18-67). Forty (69%) recipients received grafts from related donors and 18 (31%) received them from unrelated donors. Peripheral blood grafts were infused in 12 (20.7%) patients. Five-year overall survival (OS) was 80.7%. Five-year graft-versus-host disease (GVHD)/rejection-free survival was 56%. Eight (13.8%) patients experienced graft failure. The cumulative incidence of grade II-IV acute GVHD at day 100 was 14% and that of chronic GVHD at 1 year was 7%. The selection of unrelated donors and the use of peripheral blood grafts were not significant risk factors for clinically relevant GVHD or for lower OS. Recipients older than 40 years showed significantly worse OS, as observed from the results of univariate analysis. T-cell depletion in severe aplastic anemia shows low rates of GVHD and high OS, but older patients remain a group with higher risk of mortality. Long-term complications were mainly autoimmune in character.

Published
2020

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

Author

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, and Zeiser, Robert

Abstract

This corrects the article DOI: 10.1038/nm.4484.

Published
2018

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

Author

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 Müller, Thomas Niklaus, 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, and Zeiser, Robert

Subjects
hemic and lymphatic diseases, 610 Medicine & health, neoplasms, 3. Good health
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 CD8CD107aIFN-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.

5. Integrating genetic and epigenetic factors in chronic myeloid leukemia risk assessment: toward gene expression-based biomarkers

Author

S. Tiong Ong, Susan Branford, Vaidehi Krishnan, Dennis Dong Hwan Kim, Timothy P. Hughes, Krishnan, Vaidehi, Kim, Dennis Dong Hwan, Hughes, Timothy P, Branford, Susan, and Ong, S Tiong

Subjects
business.industry, medicine.drug_class, Standard treatment, Gene Expression, biomarkers, Myeloid leukemia, Risk management tools, Hematology, Computational biology, Tyrosine-kinase inhibitor, Epigenesis, Genetic, Clinical trial, chronic myeloid leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, gene expression, Humans, Medicine, Epigenetics, DNA microarray, Blast Crisis, Risk assessment, business, Protein Kinase Inhibitors, Biomarkers
Abstract

Refereed/Peer-reviewed Cancer treatment is constantly evolving from a one-size-fits-all towards bespoke approaches for each patient. In certain solid cancers, including breast and lung, tumor genome profiling has been incorporated into therapeutic decision-making. For chronic phase chronic myeloid leukemia (CML), while tyrosine kinase inhibitor therapy is the standard treatment, current clinical scoring systems cannot accurately predict the heterogeneous treatment outcomes observed in patients. Biomarkers capable of segregating patients according to outcome at diagnosis are needed to improve management, and facilitate enrollment in clinical trials seeking to prevent blast crisis transformation and improve the depth of molecular responses. To this end, gene expression (GE) profiling studies have evaluated whether GE signatures at diagnosis are clinically informative. Patient material from a variety of sources has been profiled using microarrays, RNA sequencing and, more recently, single-cell RNA sequencing. However, differences in the cell types profiled, the technologies used, and the inherent complexities associated with the interpretation of genomic data pose challenges in distilling GE datasets into biomarkers with clinical utility. The goal of this paper is to review previous studies evaluating GE profiling in CML, and explore their potential as risk assessment tools for individualized CML treatment. We also review the contribution that acquired mutations, including those seen in clonal hematopoiesis, make to GE profiles, and how a model integrating contributions of genetic and epigenetic factors in resistance to tyrosine kinase inhibitors and blast crisis transformation can define a route to GE-based biomarkers. Finally, we outline a four-stage approach for the development of GE-based biomarkers in CML.

Published
2021

6. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

Author

Dennis Dong Hwan Kim, Jane F. Apperley, Christopher A. Eide, Georgios Nteliopoulos, Sin Tiong Ong, Jerry Radich, Francois-Xavier Mahon, Jorge E. Cortes, Brian J. Druker, Satu Mustjoki, Michael J. Mauro, Charles Chuah, Susan Branford, Carlo Gambacorti-Passerini, Timothy P. Hughes, Thomas Ernst, Dong-Kee Kim, A. Hochhaus, Branford, Susan, Kim, Dennis Dong Hwan, Apperley, Jane F, Eide, Christopher A, Mustjoki, Satu, Ong, S Tiong, Nteliopoulos, Georgios, Ernst, Thomas, Chuah, Charles, Gambacorti-Passerini, Carlo, Mauro, Michael J, Druker, Brian J, Kim, Dong-Wook, Mahon, Francois-Xavier, Cortes, Jorge, Radich, Jerry P, Hochhaus, Andreas, Hughes, Timothy P, International CML Foundation Genomics Alliance, Branford, S, Kim, D, Apperley, J, Eide, C, Mustjoki, S, Ong, S, Nteliopoulos, G, Ernst, T, Chuah, C, Gambacorti-Passerini, C, Mauro, M, Druker, B, Mahon, F, Cortes, J, Radich, J, Hochhaus, A, and Hughes, T

Subjects
0301 basic medicine, Oncology, Cancer Research, Somatic evolution in cancer, Tyrosine-kinase inhibitor, 0302 clinical medicine, MED/15 - MALATTIE DEL SANGUE, hemic and lymphatic diseases, SMALL-MOLECULE INHIBITOR, Hematology, Neoplasm, chronic myeloid leukemia, BCR-ABL Positive, Tyrosine Kinases Inhibitors, CHRONIC MYELOGENOUS LEUKEMIA, Myeloid leukemia, Protein-Tyrosine Kinases, CLONAL EVOLUTION, Leukemia, Drug development, 030220 oncology & carcinogenesis, Life Sciences & Biomedicine, medicine.medical_specialty, medicine.drug_class, Immunology, Risk Assessment, Article, 03 medical and health sciences, JOINT-CONSENSUS-RECOMMENDATION, BCR-ABL MUTATIONS, Germline mutation, chronic myeloid leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, PROTEIN FAMILIES DATABASE, Protein Kinase Inhibitors, CYTOGENETIC RESPONSE, Science & Technology, CHRONIC-PHASE, business.industry, International CML Foundation Genomics Alliance, 1103 Clinical Sciences, BLAST CRISIS, SOMATIC MUTATIONS, medicine.disease, Hematopoiesis, Repressor Proteins, 030104 developmental biology, genomic analysis, Mutation, business, Genes, Neoplasm, Chronic myelogenous leukemia
Abstract

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and howto select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50%of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication.A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance. Refereed/Peer-reviewed

Published
2019

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

Author

Donald Bunjes, Sebastian Halbach, Dietmar Pfeifer, Philipp Hemmati, Robert S. Negrin, Fabio Ciceri, Jean-Yves Cahn, Markus Ditschkowski, Pavan Reddy, Kathrin Hanke, Daniela Dörfel, Susan Klaeger, Jürgen Finke, Zehan Hu, Gabriele Ihorst, Gérard Socié, Sanaz Taromi, Andreas Hochhaus, Glen A Kennedy, Omid Shah, Andreas Neubauer, Robert Thimme, Michael Schultheiss, Sabine Spath, Dietrich W. Beelen, Sandra Duquesne, Arnim Weber, Geoffrey R. Hill, Ronjon Chakraverty, Jürgen Kuball, Guido Kobbe, Nikolas von Bubnoff, Andrea S. Henden, Betul Oran, Burkhard Becher, Bernhard Kuster, Christoph Rummelt, Lena Osswald, Hartmut Bertz, Wolfgang Bethge, Eva-Maria Wagner, Arnon Nagler, Eliana Ruggiero, Saar Gill, Miguel Waterhouse, Andreas Mackensen, Dominik Bettinger, Francis Baumgartner, Florian Kuchenbauer, Anita Sarma, Takanori Teshima, Erika L. Pearce, Antonia M.S. Müller, Kathleen Stabla, John M. Magenau, Evelyn Ullrich, Nicolaus Kröger, Georg Häcker, Simone Thomas, Myriam Labopin, Ghulam J. Mufti, Jan E. Ehlert, Lutz P. Müller, Marie Follo, Dominik Wolf, Tony Andreas Müller, Michael Lübbert, Jacqueline Schnell, Christof Scheid, Takeshi Kondo, Donal P. McLornan, Thomas Pabst, Konrad Wilhelm, Chiara Bonini, Wolf Rösler, Simon Richardson, Cordula A. Jilg, Andrea Schmidts, Luca Vago, Joseph H. Antin, Annette Schmitt-Graeff, Yakup Tanriver, Michael A. Caligiuri, Wolfgang Herr, Kai-Li Yan, Lukas Braun, Daniel J. Weisdorf, Katayoun Rezvani, Giang Lam Vuong, Tilman Brummer, Stephan Meckel, Ralph Wäsch, Geoffroy Andrieux, Soroush Doostkam, Hauke Busch, Dennis Dong Hwan Kim, Sabine Gerull, Bruce R. Blazar, Robert Zeiser, Merav Bar, Flore Sicre-de-Fontbrune, Daniel Feger, Melanie Börries, Wolfgang Melchinger, Petya Apostolova, C. Leiber, Udo Holtick, Walter J.F.M. van der Velden, Renate Arnold, Rainer Claus, Justus Duyster, Nimitha R. Mathew, David O’Sullivan, Alexandros Spyridonidis, S K Metzelder, Thomas Schroeder, Jörg Halter, Johanna Haag, Friedrich Stölzel, Christoph Schmid, Anna Lena Illert, Claudia Lengerke, Björn Hackanson, Joern Dengjel, Francis Ayuk, Rainer Ordemann, Sonia Tugues, Marco Prinz, Inken Hilgendorf, Andreas Burchert, Mathew, Nimitha R, Baumgartner, Franci, Braun, Luka, 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, Marku, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst, Thoma, Schroeder, Thoma, 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, Alexandro, 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-Yve, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolau, Ayuk, Franci, 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, Andrea, 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, Sha, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andrea, Neubauer, Andrea, Beelen, Dietrich, Mackensen, Andrea, von Bubnoff, Nikola, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justu, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert

Subjects
0301 basic medicine, Sorafenib, medicine.drug_class, Interferon Regulatory Factor-7, Medizin, Graft vs Host Disease, CD8-Positive T-Lymphocytes, Article, General Biochemistry, Genetics and Molecular Biology, Tyrosine-kinase inhibitor, Mice, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Animals, Humans, Transplantation, Homologous, Medicine, ddc:610, neoplasms, Interleukin-15, business.industry, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, General Medicine, Cellular Reprogramming, medicine.disease, Activating Transcription Factor 4, 3. Good health, Gene Expression Regulation, Neoplastic, Transplantation, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, fms-Like Tyrosine Kinase 3, Tandem Repeat Sequences, Interleukin 15, 030220 oncology & carcinogenesis, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Cancer research, IRF7, business, CD8, medicine.drug
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
Full Text
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