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2. CD44v3 is a marker of invasive cancer stem cells driving metastasis in gastric carcinoma

Author

Giraud, Julie, Seeneevassen, Lornella, Rousseau, Benoit, Bouriez, Damien, Sifré, Elodie, Giese, Alban, Nguyen, Tra Ly, Tiffon, Camille, Lippi, Yannick, Azzi-Martin, Lamia, Pannequin, Julie, Ménard, Armelle, Bessède, Emilie, Staedel, Cathy, Mégraud, Francis, Belleannée, Geneviève, Lehours, Philippe, Gronnier, Caroline, Dubus, Pierre, and Varon, Christine

Published
2023
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4. Targeting metastasis-initiating cancer stem cells in gastric cancer with leukaemia inhibitory factor

Author

Seeneevassen, Lornella, primary, Zaafour, Anissa, additional, Sifré, Elodie, additional, Genevois, Coralie, additional, Nguyen, Tra Ly, additional, Pobiedonoscew, Yasmine, additional, Giese, Alban, additional, Guignard, Jérôme, additional, Tiffon, Camille, additional, Rousseau, Benoit, additional, Raymond, Anne-Aurélie, additional, Belleannée, Geneviève, additional, Boeuf, Hélène, additional, Gronnier, Caroline, additional, Martin, Océane C. B., additional, Giraud, Julie, additional, Lehours, Philippe, additional, Dubus, Pierre, additional, and Varon, Christine, additional

Published
2024
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8. CD44v3 is a marker of invasive cancer stem cells driving metastasis in gastric carcinoma

Author

Giraud, Julie, primary, Seeneevassen, Lornella, additional, Rousseau, Benoit, additional, Bouriez, Damien, additional, Sifré, Elodie, additional, Giese, Alban, additional, Nguyen, Tra Ly, additional, Tiffon, Camille, additional, Lippi, Yannick, additional, Azzi-Martin, Lamia, additional, Pannequin, Julie, additional, Ménard, Armelle, additional, Bessède, Emilie, additional, Staedel, Cathy, additional, Mégraud, Francis, additional, Belleannée, Geneviève, additional, Lehours, Philippe, additional, Gronnier, Caroline, additional, Dubus, Pierre, additional, and Varon, Christine, additional

Published
2022
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9. Uncovering the Anticancer Potential of Murine Cytomegalovirus against Human Colon Cancer Cells

Author

Massara*, Layal, Khairallah*, Camille, Yared, Nathalie, Pitard, Vincent, Rousseau, Benoit, Izotte, Julien, Giese, Alban, Dubus, Pierre, Gauthereau, Xavier, Déchanet-Merville*, Julie, Capone, Myriam, CNRS, ImmunoConcEpT, UMR 5164, Université de Bordeaux, Université de Bordeaux (UB), Service Commun des Animaleries, Animalerie A2, Université de Bordeaux, Bordeaux., Histologie et Pathologie Moléculaire, Université Bordeaux Segalen - Bordeaux 2, TBM-Core, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation pour la Recherche Médicale, Ligue Contre le CancerSIRIC BrioConseil Régional d'Aquitaine, CAPONE, Myriam, Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005)

Subjects
[SDV.BA] Life Sciences [q-bio]/Animal biology, viruses, [SDV.BA]Life Sciences [q-bio]/Animal biology, virus diseases, Decreased host defense, biochemical phenomena, metabolism, and nutrition, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, mCMV, lcsh:RC254-282, Article, IFN-B, hCMV, cross-species, anti-tumor potential, virotherapy, Human Colon cancer
Abstract

Human cytomegalovirus (HCMV) components are often found in tumors, but the precise relationship between HCMV and cancer remains a matter of debate. Pro-tumor functions of HCMV were described in several studies, but an association between HCMV seropositivity and reduced cancer risk was also evidenced, presumably relying on recognition and killing of cancer cells by HCMV-induced lymphocytes. This study aimed at deciphering whether CMV influences cancer development in an immune-independent manner. Using immunodeficient mice, we showed that systemic infection with murine CMV (MCMV) inhibited the growth of murine carcinomas. Surprisingly, MCMV, but not HCMV, also reduced human colon carcinoma development in vivo. In vitro, both viruses infected human cancer cells. Expression of human interferon-β (IFN-β) and nuclear domain (ND10) were induced in MCMV-infected, but not in HCMV-infected human colon cancer cells. These results suggest a decreased capacity of MCMV to counteract intrinsic defenses in the human cellular host. Finally, immunodeficient mice receiving peri-tumoral MCMV therapy showed a reduction of human colon cancer cell growth, albeit no clinical sign of systemic virus dissemination was evidenced. Our study, which describes a selective advantage of MCMV over HCMV to control human colon cancer, could pave the way for the development of CMV-based therapies against cancer. Keywords: mCMV, hCMV, Anti-tumor potential, Decreased host defense, Human Colon cancer, Cross-species, Virotherapy, IFN-B

Published
2020

10. Alzheimer’s Disease and Helicobacter pylori Infection: Inflammation from Stomach to Brain?

Author

Albaret, Guillaume, primary, Sifré, Elodie, additional, Floch, Pauline, additional, Laye, Sophie, additional, Aubert, Agnès, additional, Dubus, Pierre, additional, Azzi-Martin, Lamia, additional, Giese, Alban, additional, Salles, Nathalie, additional, Mégraud, Francis, additional, Varon, Christine, additional, Lehours, Philippe, additional, and Roubaud-Baudron, Claire, additional

Published
2020
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11. Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

Author

González, Andrés, primary, Casado, Javier, additional, Chueca, Eduardo, additional, Salillas, Sandra, additional, Velázquez-Campoy, Adrián, additional, Espinosa Angarica, Vladimir, additional, Bénejat, Lucie, additional, Guignard, Jérome, additional, Giese, Alban, additional, Sancho, Javier, additional, Lehours, Philippe, additional, and Lanas, Ángel, additional

Published
2019
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12. Whole-Genome Sequencing and Bioinformatics as Pertinent Tools to Support Helicobacteracae Taxonomy, Based on Three Strains Suspected to Belong to Novel Helicobacter Species

Author

Berthenet, Elvire, primary, Bénéjat, Lucie, additional, Ménard, Armelle, additional, Varon, Christine, additional, Lacomme, Sabrina, additional, Gontier, Etienne, additional, Raymond, Josette, additional, Boussaba, Ouahiba, additional, Toulza, Olivier, additional, Ducournau, Astrid, additional, Buissonnière, Alice, additional, Giese, Alban, additional, Megraud, Francis, additional, Bessède, Emilie, additional, Jehanne, Quentin, additional, and Lehours, Philippe, additional

Published
2019
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13. Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL

Author

Dumas, Pierre-Yves, Naudin, Cécile, Martin-Lannerée, Séverine, Izac, Brigitte, Casetti, Luana, Mansier, Olivier, Rousseau, Benoît, Artus, Alexandre, Dufossée, Mélody, Giese, Alban, Dubus, Pierre, Pigneux, Arnaud, Praloran, Vincent, Bidet, Audrey, Villacreces, Arnaud, Guitart, Amélie, Milpied, Noël, Kosmider, Olivier, Vigon, Isabelle, Desplat, Vanessa, Dusanter-Fourt, Isabelle, Pasquet, Jean-Max, CHU Bordeaux, Service d'Hématologie Clinique et Thérapie cellulaire, F-33000, Bordeaux., Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris., Service de Biologie des Tumeurs and Laboratoire d'Hématologie Biologique, Centre Hospitalo-Universitaire CHU Bordeaux, F-33000, Bordeaux., Service Commun des Animaleries, Animalerie A2, Université de Bordeaux, Bordeaux., TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Paris, France., Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris isabelle.dusanter@inserm.fr., and Vigon, Isabelle

Subjects
Acute Myeloid Leukemia, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Phenylurea Compounds, [SDV]Life Sciences [q-bio], Hematopoietic Stem Cell Transplantation, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Article, Up-Regulation, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, fms-Like Tyrosine Kinase 3, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, embryonic structures, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], STAT5 Transcription Factor, Tumor Microenvironment, Humans, Benzothiazoles, Hypoxia, ComputingMilieux_MISCELLANEOUS
Abstract

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.

Published
2019

14. STAT5-and hypoxia-dependent upregulation of AXL

Author

DUMAS, Pierre-Yves, NAUDIN, Cécile, MARTIN-LANNERÉE, Séverine, IZAC, Brigitte, CASETTI, Luana, MANSIER, Olivier, ROUSSEAU, Benoît, ARTUS, Alexandre, DUFOSSÉE, Mélody, GIESE, Alban, DUBUS, Pierre, PIGNEUX, Arnaud, PRALORAN, Vincent, BIDET, Audrey, VILLACRECES, Arnaud, GUITART, Amélie, MILPIED, Noël, KOSMIDER, Olivier, VIGON, Isabelle, DESPLAT, Vanessa, DUSANTER-FOURT, Isabelle, and PASQUET, Jean-Max

Subjects
Article RECHERCHE
Published
2019

15. Orthotopic Patient-Derived Xenografts of Gastric Cancer to Decipher Drugs Effects on Cancer Stem Cells and Metastatic Dissemination

Author

Giraud, Julie, primary, Bouriez, Damien, additional, Seeneevassen, Lornella, additional, Rousseau, Benoit, additional, Sifré, Elodie, additional, Giese, Alban, additional, Mégraud, Francis, additional, Lehours, Philippe, additional, Dubus, Pierre, additional, Gronnier, Caroline, additional, and Varon, Christine, additional

Published
2019
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16. Regulatory T cells may participate in Helicobacter pylori persistence in gastric MALT lymphoma: lessons from an animal model

Author

Laur, Amandine Marine, Floch, Pauline, Chambonnier, Lucie, Benejat, Lucie, Korolik, Victoria, Giese, Alban, Dubus, Pierre, Mégraud, Francis, Bandeira, Antonio, Lehours, Philippe, Infection à helicobacter, inflammation et cancer, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bactériologie, CHU Bordeaux [Bordeaux], insitute for glycomics, Griffith University [Brisbane], Histologie et Pathologie Moléculaire, Université Bordeaux Segalen - Bordeaux 2, Biologie des Populations Lymphocytaires, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Alban Giese and the Experimental Histology unit were funded by the Cancéropôle Grand Sud Ouest, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
regulatory T cell, Real-Time Polymerase Chain Reaction, T-Lymphocytes, Regulatory, Helicobacter Infections, Immunoenzyme Techniques, Mice, MESH: Lymphoma, Non-Hodgkin, Stomach Neoplasms, MESH: Reverse Transcriptase Polymerase Chain Reaction, Animals, MESH: Animals, RNA, Messenger, MALT lymphoma, MESH: Immunoenzyme Techniques, MESH: Lymphoma, B-Cell, Marginal Zone, MESH: Mice, MESH: RNA, Messenger, Helicobacter pylori, Reverse Transcriptase Polymerase Chain Reaction, MESH: Real-Time Polymerase Chain Reaction, Lymphoma, Non-Hodgkin, animal model, MESH: Helicobacter Infections, MESH: T-Lymphocytes, Regulatory, Lymphoma, B-Cell, Marginal Zone, MESH: Stomach Neoplasms, Disease Models, Animal, MESH: Gastric Mucosa, Gastric Mucosa, MESH: Helicobacter pylori, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Disease Models, Animal, Research Paper
Abstract

International audience; It has been postulated that the emergence of autoimmune gastritis in neonatal thymectomised (d3Tx) BALB/c mice may be a consequence of post-surgery deficit in Tregs. In this study, previously obtained samples from d3Tx mice were used in order to determine whether thymectomy creates a deficit in this T cell subset thereby allowing the emergence of autoimmune phenomena as a prerequisite for GML. The splenic Treg reserve and the local recruitment of these cells in the gastric mucosa were investigated using complementary molecular and immunohistochemistry approaches. Higher Foxp3/CD3 ratios were found in the spleen of non-infected d3Tx mice compared to non-thymectomised (NTx) controls. These results indicate a relative enrichment of Tregs following thymectomy in adult mice. The absence of Treg depletion in d3Tx mice is in line with the absence of auto-immune gastritis in non-infected d3Tx mice. Higher levels of T cell and Treg infiltration were also found in the stomach of GML-developing d3Tx mice versus NTx mice. Surprisingly, inflammatory scores inversely correlated with the bacterial inoculum. The presence of a small Treg containing compartment among gastric biopsies of GML developing d3Tx mice may play a role in perseverance of a minimal bacterial numbers thereby maintaining an antigen-dependent stimulation and proliferation.

Published
2016

17. A New Animal Model of Gastric Lymphomagenesis

Author

Floch, Pauline, primary, Izotte, Julien, additional, Guillemaud, Julien, additional, Sifré, Elodie, additional, Costet, Pierre, additional, Rousseau, Benoit, additional, Laur, Amandine Marine, additional, Giese, Alban, additional, Korolik, Victoria, additional, Mégraud, Francis, additional, Dubus, Pierre, additional, Hahne, Michael, additional, and Lehours, Philippe, additional

Published
2017
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19. Unr defines a novel class of nucleoplasmic reticulum, involved in mRNA translation

Author

Saltel, Frédéric, primary, Giese, Alban, additional, Azzi, Lamia, additional, Elatmani, Habiba, additional, Costet, Pierre, additional, Ezzoukhry, Zakaria, additional, Dugot-Senant, Nathalie, additional, Miquerol, Lucile, additional, Boussadia, Oréda, additional, Wodrich, Harald, additional, Dubus, Pierre, additional, and Jacquemin-Sablon, Hélène, additional

Published
2017
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20. Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro

Author

Bessède, Emilie, primary, Molina, Silvia, additional, Amador, Luis Acuña, additional, Dubus, Pierre, additional, Staedel, Cathy, additional, Chambonnier, Lucie, additional, Buissonnière, Alice, additional, Sifré, Elodie, additional, Giese, Alban, additional, Bénéjat, Lucie, additional, Rousseau, Benoît, additional, Costet, Pierre, additional, Sacks, David B., additional, Mégraud, Francis, additional, and Varon, Christine, additional

Published
2016
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21. γδ T Cells Confer Protection against Murine Cytomegalovirus (MCMV).

Author

Khairallah, Camille, Netzer, Sonia, Villacreces, Arnaud, Juzan, Marina, Rousseau, Benoît, Dulanto Magallanes, Sara Adriana, Giese, Alban, Costet, Pierre, Praloran, Vincent, Moreau, Jean François, Dubus, Pierre, Vermijlen, David, Dechanet-Merville, Julie, Capone, Myriam, Khairallah, Camille, Netzer, Sonia, Villacreces, Arnaud, Juzan, Marina, Rousseau, Benoît, Dulanto Magallanes, Sara Adriana, Giese, Alban, Costet, Pierre, Praloran, Vincent, Moreau, Jean François, Dubus, Pierre, Vermijlen, David, Dechanet-Merville, Julie, and Capone, Myriam

Abstract

Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune-compromised patients. γδ T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 αβ and/or γδ T cell-deficient mice, we here show that γδ T cells are as competent as αβ T cells to protect mice from CMV-induced death. γδ T cell-mediated protection involved control of viral load and prevented organ damage. γδ T cell recovery by bone marrow transplant or adoptive transfer experiments rescued CD3ε-/- mice from CMV-induced death confirming the protective antiviral role of γδ T cells. As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells. This response was observed in the liver and lungs and implicated both CD27+ and CD27- γδ T cells. NK cells were the largely preponderant producers of IFNγ and cytotoxic granules throughout the infection, suggesting that the protective role of γδ T cells did not principally rely on either of these two functions. Finally, γδ T cells were strikingly sufficient to fully protect Rag-/-γc-/- mice from death, demonstrating that they can act in the absence of B and NK cells. Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αβ T cell compromised patients., info:eu-repo/semantics/published

Published
2015

23. An Eighteen-Month Helicobacter Infection Does Not Induce Amyloid Plaques or Neuroinflammation in Brains of Wild Type C57BL/6J Mice

Author

Roubaud Baudron, Claire, primary, Chambonnier, Lucie, additional, Buissionnière, Alice, additional, Giese, Alban, additional, Macrez, Nathalie, additional, Cho, Yoon, additional, Fénelon, Valérie, additional, Blaszczyk, Lucie, additional, Dubus, Pierre, additional, Lehours, Philippe, additional, Mégraud, Francis, additional, Salles, Nathalie, additional, and Varon, Christine, additional

Published
2015
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24. γδ T Cells Confer Protection against Murine Cytomegalovirus (MCMV)

Author

Khairallah, Camille, primary, Netzer, Sonia, additional, Villacreces, Arnaud, additional, Juzan, Marina, additional, Rousseau, Benoît, additional, Dulanto, Sara, additional, Giese, Alban, additional, Costet, Pierre, additional, Praloran, Vincent, additional, Moreau, Jean-François, additional, Dubus, Pierre, additional, Vermijlen, David, additional, Déchanet-Merville, Julie, additional, and Capone, Myriam, additional

Published
2015
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25. Uncovering the Anticancer Potential of Murine Cytomegalovirus against Human Colon Cancer Cells.

Author

Massara L, Khairallah C, Yared N, Pitard V, Rousseau B, Izotte J, Giese A, Dubus P, Gauthereau X, Déchanet-Merville J, and Capone M

Abstract

Human cytomegalovirus (HCMV) components are often found in tumors, but the precise relationship between HCMV and cancer remains a matter of debate. Pro-tumor functions of HCMV were described in several studies, but an association between HCMV seropositivity and reduced cancer risk was also evidenced, presumably relying on recognition and killing of cancer cells by HCMV-induced lymphocytes. This study aimed at deciphering whether CMV influences cancer development in an immune-independent manner. Using immunodeficient mice, we showed that systemic infection with murine CMV (MCMV) inhibited the growth of murine carcinomas. Surprisingly, MCMV, but not HCMV, also reduced human colon carcinoma development in vivo . In vitro , both viruses infected human cancer cells. Expression of human interferon-β ( IFN-β ) and nuclear domain ( ND10 ) were induced in MCMV-infected, but not in HCMV-infected human colon cancer cells. These results suggest a decreased capacity of MCMV to counteract intrinsic defenses in the human cellular host. Finally, immunodeficient mice receiving peri-tumoral MCMV therapy showed a reduction of human colon cancer cell growth, albeit no clinical sign of systemic virus dissemination was evidenced. Our study, which describes a selective advantage of MCMV over HCMV to control human colon cancer, could pave the way for the development of CMV-based therapies against cancer., (© 2020 The Author(s).)

Published
2020
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26. Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL.

Author

Dumas PY, Naudin C, Martin-Lannerée S, Izac B, Casetti L, Mansier O, Rousseau B, Artus A, Dufossée M, Giese A, Dubus P, Pigneux A, Praloran V, Bidet A, Villacreces A, Guitart A, Milpied N, Kosmider O, Vigon I, Desplat V, Dusanter-Fourt I, and Pasquet JM

Subjects
Cell Hypoxia, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Leukemic drug effects, Humans, K562 Cells, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, STAT5 Transcription Factor genetics, Up-Regulation drug effects, fms-Like Tyrosine Kinase 3 genetics, Axl Receptor Tyrosine Kinase, Benzothiazoles pharmacology, Drug Resistance, Neoplasm, Leukemia, Myeloid, Acute metabolism, Phenylurea Compounds pharmacology, Proto-Oncogene Proteins biosynthesis, Receptor Protein-Tyrosine Kinases biosynthesis, STAT5 Transcription Factor metabolism, Tumor Microenvironment, fms-Like Tyrosine Kinase 3 metabolism
Abstract

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones., (Copyright© 2019 Ferrata Storti Foundation.)

Published
2019
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27. Regulatory T cells may participate in Helicobacter pylori persistence in gastric MALT lymphoma: lessons from an animal model.

Author

Laur AM, Floch P, Chambonnier L, Benejat L, Korolik V, Giese A, Dubus P, Mégraud F, Bandeira A, and Lehours P

Subjects
Animals, Gastric Mucosa microbiology, Gastric Mucosa pathology, Helicobacter Infections microbiology, Helicobacter Infections pathology, Immunoenzyme Techniques, Lymphoma, B-Cell, Marginal Zone microbiology, Lymphoma, B-Cell, Marginal Zone pathology, Lymphoma, Non-Hodgkin microbiology, Lymphoma, Non-Hodgkin pathology, Mice, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Stomach Neoplasms microbiology, Stomach Neoplasms pathology, Disease Models, Animal, Gastric Mucosa immunology, Helicobacter Infections immunology, Helicobacter pylori immunology, Lymphoma, B-Cell, Marginal Zone immunology, Lymphoma, Non-Hodgkin immunology, Stomach Neoplasms immunology, T-Lymphocytes, Regulatory immunology
Abstract

It has been postulated that the emergence of autoimmune gastritis in neonatal thymectomised (d3Tx) BALB/c mice may be a consequence of post-surgery deficit in Tregs. In this study, previously obtained samples from d3Tx mice were used in order to determine whether thymectomy creates a deficit in this T cell subset thereby allowing the emergence of autoimmune phenomena as a prerequisite for GML. The splenic Treg reserve and the local recruitment of these cells in the gastric mucosa were investigated using complementary molecular and immunohistochemistry approaches. Higher Foxp3/CD3 ratios were found in the spleen of non-infected d3Tx mice compared to non-thymectomised (NTx) controls. These results indicate a relative enrichment of Tregs following thymectomy in adult mice. The absence of Treg depletion in d3Tx mice is in line with the absence of auto-immune gastritis in non-infected d3Tx mice. Higher levels of T cell and Treg infiltration were also found in the stomach of GML-developing d3Tx mice versus NTx mice. Surprisingly, inflammatory scores inversely correlated with the bacterial inoculum. The presence of a small Treg containing compartment among gastric biopsies of GML developing d3Tx mice may play a role in perseverance of a minimal bacterial numbers thereby maintaining an antigen-dependent stimulation and proliferation.

Published
2016
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28. An Eighteen-Month Helicobacter Infection Does Not Induce Amyloid Plaques or Neuroinflammation in Brains of Wild Type C57BL/6J Mice.

Author

Baudron CR, Chambonnier L, Buissionnière A, Giese A, Macrez N, Cho Y, Fénelon V, Blaszczyk L, Dubus P, Lehours P, Mégraud F, Salles N, and Varon C

Subjects
Amyloid beta-Peptides metabolism, Animals, Disease Models, Animal, Mice, Inbred C57BL, Neuroimmunomodulation, Plaque, Amyloid immunology, Plaque, Amyloid pathology, Brain immunology, Brain pathology, Helicobacter Infections immunology, Helicobacter Infections pathology, Helicobacter felis, Helicobacter pylori
Abstract

There is increasing evidence to support the role of infectious agents in the progression of Alzheimer's disease (AD), especially Helicobacter pylori (H. pylori). The impact of Helicobacter infection on the brain of non-AD predisposed mice was studied. For that, C57BL/6J mice were infected by oral gavage with H. pylori SS1 (n = 6) and Helicobacter felis (H. felis) (n=6) or not infected (n = 6) for evaluation of neuroinflammation (anti-GFAP and anti-iba1 immunohistochemistry) and amyloid-β deposition (thioflavin-S stain and anti-Aβ immunohistochemistry). After 18-month of infection, H. pylori SS1 and H. felis infection induced a strong gastric inflammation compared to non-infected mice, but did not induce brain neuroinflammation or amyloid-β deposition.

Published
2015
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