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1. T-cell acute lymphoblastic leukemia progression is supported by inflammatory molecules including hepatocyte growth factor

Author: Charly Le Maout, Lucine Fahy, Laurent Renou, Caroline Devanand, Charlotte Duwat, Vilma Barroca, Morgane Le Gall, Paola Ballerini, Arnaud Petit, Julien Calvo, Benjamin Uzan, Françoise Pflumio, and Vanessa Petit
Subjects: T-ALL, Inflammation, Myeloid cells, Molecule secretion, HGF, Therapeutics. Pharmacology, RM1-950
Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL treatment includes chemotherapy with strong side effects, and patients that undergo relapse display poor prognosis. Although cell-intrinsic oncogenic pathways are well-studied, the tumor microenvironment, like inflammatory cellular and molecular components is less explored in T-ALL. We sought to determine the composition of the inflammatory microenvironment induced by T-ALL, and its role in T-ALL progression. We show in two mouse T-ALL cell models that T-ALLs enhance blood neutrophils and resident monocytes, accompanied with a plasmatic acute secretion of inflammatory molecules. Depleting neutrophils using anti-Ly6G treatment or resident monocytes by clodronate liposomes treatment does not modulate plasmatic inflammatory molecule secretion and mice survival. However, inhibiting the secretion of inflammatory molecules by microenvironment with NECA, an agonist of adenosine receptors, diminishes T-ALL progression enhancing mouse survival. We uncovered Hepatocyte Growth Factor (HGF), T-ALL-driven and the most decreased molecule with NECA, as a potential therapeutic target in T-ALL. Altogether, we identified a signature of inflammatory molecules that can potentially be involved in T-ALL evolution and uncovered HGF/cMET pathway as important to target for limiting T-ALL progression.
Published: 2024
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2. A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors

Author: Maria Eugénia Marques Da Costa, Sakina Zaidi, Jean-Yves Scoazec, Robin Droit, Wan Ching Lim, Antonin Marchais, Jerome Salmon, Sarah Cherkaoui, Raphael J. Morscher, Anouchka Laurent, Sébastien Malinge, Thomas Mercher, Séverine Tabone-Eglinger, Isabelle Goddard, Francoise Pflumio, Julien Calvo, Francoise Redini, Natacha Entz-Werlé, Aroa Soriano, Alberto Villanueva, Stefano Cairo, Pascal Chastagner, Massimo Moro, Cormac Owens, Michela Casanova, Raquel Hladun-Alvaro, Pablo Berlanga, Estelle Daudigeos-Dubus, Philippe Dessen, Laurence Zitvogel, Ludovic Lacroix, Gaelle Pierron, Olivier Delattre, Gudrun Schleiermacher, Didier Surdez, and Birgit Geoerger
Subjects: Biology (General), QH301-705.5
Abstract: Abstract Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies.
Published: 2023
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3. CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia

Author: Awatef Allouch, Laurent Voisin, Yanyan Zhang, Syed Qasim Raza, Yann Lecluse, Julien Calvo, Dorothée Selimoglu-Buet, Stéphane de Botton, Fawzia Louache, Françoise Pflumio, Eric Solary, and Jean-Luc Perfettini
Subjects: Science
Abstract: Inducing phagocytic capacities of tumour-associated macrophages to eliminate cancer cells is a promising immunotherapy. Here, the authors show that engineered macrophages overexpressing CDKN1A/p21 reduce leukaemic tumour burden and increase survival in preclinical mouse models of human T-ALL.
Published: 2022
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4. Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia

Author: Tra Ly Nguyen, Marie‐Julie Nokin, Silvia Terés, Mercedes Tomé, Clément Bodineau, Oriane Galmar, Jean‐Max Pasquet, Benoit Rousseau, Sebastian vanLiempd, Juan Manuel Falcon‐Perez, Elodie Richard, Elodie Muzotte, Hamid‐Reza Rezvani, Muriel Priault, Marion Bouchecareilh, Isabelle Redonnet‐Vernhet, Julien Calvo, Benjamin Uzan, Françoise Pflumio, Patricia Fuentes, Maria L. Toribio, Abdel‐Majid Khatib, Pierre Soubeyran, Piedad del Socorro Murdoch, and Raúl V. Durán
Subjects: glutamine, glutamine synthetase, metabolic addiction, mTORC1, Notch1, T‐cell acute lymphoblastic leukemia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The cellular receptor Notch1 is a central regulator of T‐cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T‐cell acute lymphoblastic leukemia (T‐ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T‐ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti‐Notch therapies in T‐ALL models. In this work, we report that Notch1 upregulation in T‐ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1‐driven T‐ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1‐induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1‐driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1‐driven leukemia.
Published: 2021
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5. Human hematopoietic stem/progenitor cells display reactive oxygen species-dependent long-term hematopoietic defects after exposure to low doses of ionizing radiations

Author: Elia Henry, Inès Souissi-Sahraoui, Margaux Deynoux, Andréas Lefèvre, Vilma Barroca, Anna Campalans, Véronique Ménard, Julien Calvo, Françoise Pflumio, and Marie-Laure Arcangeli
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Hematopoietic stem cells are responsible for life-long blood cell production and are highly sensitive to exogenous stresses. The effects of low doses of ionizing radiations on radiosensitive tissues such as the hematopoietic tissue are still unknown despite their increasing use in medical imaging. Here, we study the consequences of low doses of ionizing radiations on differentiation and self-renewal capacities of human primary hematopoietic stem/progenitor cells (HSPC). We found that a single 20 mGy dose impairs the hematopoietic reconstitution potential of human HSPC but not their differentiation properties. In contrast to high irradiation doses, low doses of irradiation do not induce DNA double strand breaks in HSPC but, similar to high doses, induce a rapid and transient increase of reactive oxygen species (ROS) that promotes activation of the p38MAPK pathway. HSPC treatment with ROS scavengers or p38MAPK inhibitor prior exposure to 20 mGy irradiation abolishes the 20 mGy-induced defects indicating that ROS and p38MAPK pathways are transducers of low doses of radiation effects. Taken together, these results show that a 20 mGy dose of ionizing radiation reduces the reconstitution potential of HSPC suggesting an effect on the self-renewal potential of human hematopoietic stem cells and pinpointing ROS or the p38MAPK as therapeutic targets. Inhibition of ROS or the p38MAPK pathway protects human primary HSPC from low-dose irradiation toxicity.
Published: 2020
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6. Hypoxia Regulates Lymphoid Development of Human Hematopoietic Progenitors

Author: Sara Chabi, Benjamin Uzan, Irina Naguibneva, Julien Rucci, Lucine Fahy, Julien Calvo, Marie-Laure Arcangeli, Frédéric Mazurier, Françoise Pflumio, and Rima Haddad
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Hypoxia plays a major role in the physiology of hematopoietic and immune niches. Important clues from works in mouse have paved the way to investigate the role of low O2 levels in hematopoiesis. However, whether hypoxia impacts the initial steps of human lymphopoiesis remains unexplored. Here, we show that hypoxia regulates cellular and metabolic profiles of umbilical cord blood (UCB)-derived hematopoietic progenitor cells. Hypoxia more specifically enhances in vitro lymphoid differentiation potentials of lymphoid-primed multipotent progenitors (LMPPs) and pro-T/natural killer (NK) cells and in vivo B cell potential of LMPPs. In accordance, hypoxia exacerbates the lymphoid gene expression profile through hypoxia-inducible factor (HIF)-1α (for LMPPs) and HIF-2α (for pro-T/NK). Moreover, loss of HIF-1/2α expression seriously impedes NK and B cell production from LMPPs and pro-T/NK. Our study describes how hypoxia contributes to the lymphoid development of human progenitors and reveals the implication of the HIF pathway in LMPPs and pro-T/NK-cell lymphoid identities. : Chabi et al. show that low oxygen levels promote the development of human lymphoid cells from umbilical cord blood progenitors. The work also highlights how hypoxia-inducible factors, the major actors of hypoxia cell response, are involved in the early steps of human lymphopoiesis by supporting cell differentiation and production.
Published: 2019
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7. Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia

Author: Xavier Cahu, Julien Calvo, Sandrine Poglio, Nais Prade, Benoit Colsch, Marie-Laure Arcangeli, Thierry Leblanc, Arnaud Petit, Frederic Baleydier, Andre Baruchel, Judith Landman-Parker, Christophe Junot, Jerome Larghero, Paola Ballerini, Eric Delabesse, Benjamin Uzan, and Francoise Pflumio
Subjects: Specialties of internal medicine, RC581-951
Abstract: Abstract: T-cell acute lymphoblastic leukemia (T-ALL) expands in various bone marrow (BM) sites of the body. We investigated whether different BM sites could differently modulate T-ALL propagation using in vivo animal models. We observed that mouse and human T-ALL develop slowly in the BM of tail vertebrae compared with the BM from thorax vertebrae. T-ALL recovered from tail BM displays lower cell-surface marker expression and decreased metabolism and cell-cycle progression, demonstrating a dormancy phenotype. Functionally, tail-derived T-ALL exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are noncell-autonomous because T-ALL from tail and thorax shares identical genomic abnormalities and functional disparities disappear in vivo and in prolonged in vitro assays. Importantly tail-derived T-ALL displays higher intrinsic resistance to cell-cycle–related drugs (ie, vincristine sulfate and cytarabine). Of note, T-ALL recovered from gonadal adipose tissues or from cocultures with adipocytes shares metabolic, cell-cycle, and phenotypic or chemoresistance features, with tail-derived T-ALL suggesting adipocytes may participate in the tail BM imprints on T-ALL. Altogether these results demonstrate that BM sites differentially orchestrate T-ALL propagation stamping specific features to leukemic cells such as quiescence and decreased response to cell-cycle–dependent chemotherapy.
Published: 2017
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8. Homeobox protein TLX3 activates miR-125b expression to promote T-cell acute lymphoblastic leukemia

Author: Laurent Renou, Pierre-Yves Boelle, Caroline Deswarte, Salvatore Spicuglia, Aissa Benyoucef, Julien Calvo, Benjamin Uzan, Mohamed Belhocine, Agata Cieslak, Judith Landman-Parker, Andre Baruchel, Vahid Asnafi, Françoise Pflumio, Paola Ballerini, and Irina Naguibneva
Subjects: Specialties of internal medicine, RC581-951
Abstract: Abstract: The oncogenic mechanisms driven by aberrantly expressed transcription factors in T-cell acute leukemia (T-ALL) are still elusive. MicroRNAs (miRNAs) play an important role in normal development and pathologies. Here, we examined the expression of 738 miRNA species in 41 newly diagnosed pediatric T-ALLs and in human thymus-derived cells. We found that expression of 2 clustered miRNAs, miR-125b/99a, peaks in primitive T cells and is upregulated in the T leukemia homeobox 3 (TLX3)–positive subtype of T-ALL. Using loss- and gain-of-function approaches, we established functional relationships between TLX3 and miR-125b. Both TLX3 and miR-125b support in vitro cell growth and in vivo invasiveness of T-ALL. Besides, ectopic expression of TLX3 or miR-125b in human hematopoietic progenitor cells enhances production of T-cell progenitors and favors their accumulation at immature stages of T-cell development resembling the differentiation arrest observed in TLX3 T-ALL. Ectopic miR-125b also remarkably accelerated leukemia in a xenograft model, suggesting that miR125b is an important mediator of the TLX3-mediated transformation program that takes place in immature T-cell progenitors. Mechanistically, TLX3-mediated activation of miR-125b may impact T-cell differentiation in part via repression of Ets1 and CBFβ genes, 2 regulators of T-lineage. Finally, we established that TLX3 directly regulates miR-125b production through binding and transactivation of LINC00478, a long noncoding RNA gene, which is the host of miR-99a/Let-7c/miR-125b. Altogether, our results reveal an original functional link between TLX3 and oncogenic miR-125b in T-ALL development.
Published: 2017
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9. Interleukin‐18 produced by bone marrow‐derived stromal cells supports T‐cell acute leukaemia progression

Author: Benjamin Uzan, Sandrine Poglio, Bastien Gerby, Ching‐Lien Wu, Julia Gross, Florence Armstrong, Julien Calvo, Xavier Cahu, Caroline Deswarte, Florent Dumont, Diana Passaro, Corinne Besnard‐Guérin, Thierry Leblanc, André Baruchel, Judith Landman‐Parker, Paola Ballerini, Véronique Baud, Jacques Ghysdael, Frédéric Baleydier, Francoise Porteu, and Francoise Pflumio
Subjects: IL‐18, inflammation, stromal cells, T‐ALL, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract Development of novel therapies is critical for T‐cell acute leukaemia (T‐ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T‐ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T‐ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when T‐ALL cells were cultured with ERK1/2‐knockdown stromal cells or with conditioned medium from MEKi‐treated stromal cells. Microarray analysis identified interleukin 18 (IL‐18) as transcriptionally up‐regulated in MEKi‐treated MS5 cells. Recombinant IL‐18 promoted T‐ALL growth in vitro, whereas the loss of function of IL‐18 receptor in T‐ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL‐18R was activated by IL‐18 in blast cells. IL‐18 circulating levels were increased in T‐ALL‐xenografted mice and also in T‐ALL patients in comparison with controls. This study uncovers a novel role of the pro‐inflammatory cytokine IL‐18 and outlines the microenvironment involvement in human T‐ALL development.
Published: 2014
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10. Assessment of human multi-potent hematopoietic stem/progenitor cell potential using a single in vitro screening system.

Author: Julien Calvo, Aissa BenYoucef, Jan Baijer, Marie-Christine Rouyez, and Francoise Pflumio
Subjects: Medicine, Science
Abstract: Hematopoietic stem cells are responsible for the generation of the entire blood system through life. This characteristic relies on their ability to self renew and on their multi-potentiality. Thus quantification of the number of hematopoietic stem cells in a given cell population requires to show both properties in the studied cell populations. Although xenografts models that support human hematopoietic stem cells have been described, such in vivo experimental systems remain restrictive for high throughput screening purposes for example. In this work we developed a conditional tetracycline inducible system controlling the expression of the human NOTCH ligand Delta-like 1 in the murine stromal MS5 cells. We cultured hematopoietic immature cells enriched in progenitor/stem cells in contact with MS5 cells that conditionally express Delta-like 1, in conditions designed to generate multipotential lineage differentiation. We show that upon induction or repression of DL1 expression during co-culture, human immature CD34(+)CD38(-/low)(CD45RA(-)CD90(+)) cells can express their B, T, NK, granulo/monocytic and erythroid potentials in a single well, and at the single cell level. We also document the interference of low NOTCH activation with human B and myelo/erythroid lymphoid differentiation. This system represents a novel tool to precisely quantify human hematopoietic immature cells with both lymphoid and myeloid potentials.
Published: 2012
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11. Antiretroviral treatment start-time during primary SIV(mac) infection in macaques exerts a different impact on early viral replication and dissemination.

Author: Pierre Sellier, Abdelkrim Mannioui, Olivier Bourry, Nathalie Dereuddre-Bosquet, Benoit Delache, Patricia Brochard, Julien Calvo, Sophie Prévot, and Pierre Roques
Subjects: Medicine, Science
Abstract: BACKGROUND: The time of infection is rarely known in human cases; thus, the effects of delaying the initiation of antiretroviral therapy (ART) on the peripheral viral load and the establishment of viral reservoirs are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Six groups of macaques, infected intravenously with SIV(mac251), were given placebo or antiretroviral therapy to explore reservoir establishment; macaques were treated for 2 weeks, with treatment starting 4 hours, 7 or 14 days after infection. Viral replication and dissemination were measured in the gut (rectum), in the lung and in blood and lymphoid tissues (peripheral lymph nodes), by quantifying viral RNA, DNA and 2LTR circles. We used immunohistochemistry (CD4 and CD68) to assess the impact of these treatments on the relative amount of virus target cells in tissue. Treatment that was started 4 hours post-infection (pi) decreased viral replication and dissemination in blood and tissue samples, which were assessed on day 14 (RNA/DNA/2LTR circles). The virus remained detectable and lymphoid tissues were activated in LN and the gut in both placebo- and ART-treated animals. Viral RNA in plasma continued to be lower in macaques treated seven days after infection; however, this was not the case for viral DNA in peripheral blood mononuclear cells. There was a small but significant difference in RNA and DNA levels in tissues between placebo- and ART-treated animals on day 21. When started 14 days after infection, treatment resulted in a limited decrease in the plasma viral load. CONCLUSIONS: Treatment that was started 4 hours after infection significantly reduced viral replication and dissemination. When started 7 days after infection, it was of slight virological benefit in peripheral blood and in tissues, and treatment was even less effective if started 14 days pi. These data favor starting ART no longer than one week after intravenous SIV(mac251) exposure.
Published: 2010
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12. β-Catenin and its new partner FOXO3 shake T-ALL

Author: Julien Calvo and Françoise Pflumio
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2023

13. Supplementary Table 2 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: KEGG Pathway Enrichment Analysis of Differential Expressed Genes Between Thymus and T-ALL
Published: 2023

14. Supplementary Table 3 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: KEGG Pathway Enrichment Analysis of Differential Expressed Genes Between CD4 T-Cells and T-ALL
Published: 2023

15. Data from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL.Significance:Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery.This article is highlighted in the In This Issue feature, p. 1241
Published: 2023

16. Supplementary Table 14 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: Differential Gene Expression and Enrichment Analysis Between Control and shSRSF6-Treated JURKAT Cells
Published: 2023

17. Supplementary Figures S1-15 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: Supplementary Figures S1-S15 and Legends
Published: 2023

18. Supplementary Table 7 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: Alternative Spliced Genes Between HR and NHR T-ALL Patients and Enrichment Analysis
Published: 2023

19. Supplementary Table 8 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: SRSF Family Proteins Essentiality in Tumor Cell Lines
Published: 2023

20. Supplementary Table 6 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: Motif Analysis of Skip Exon Events in T-ALL Compared to CD3 T Cells
Published: 2023

21. Supplementary Table 9 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: CRISP Screens of RNA Binding Proteins in T-ALL
Published: 2023

22. Supplementary Table 4 from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Author: Panagiotis Ntziachristos, Giuseppe Basso, Benedetta Accordi, Francoise Pflumio, Rama K. Mishra, Keng Boon Wee, Aristotelis Tsirigos, Adriana Heguy, Ernesto Guccione, Young Ah Goo, Iannis Aifantis, Tom Taghon, Pieter Van Vlierberghe, Bruno Palhais, Ping Zhu, Marc L. Mendillo, Hiam Abdala-Valencia, Yuliya Politanska, Irawati Kandela, Hu Li, Cheng Zhang, Maddalena Paganin, Silvia Bresolin, Radhika Rawat, Emily J. Rendleman, David R. Amici, Yoh-Hei Takahashi, Qi Jin, Szymon K. Filip, George Yacu, Limin Sun, Anna Kuchmiy, Christian Marier, Tommaso Tabaglio, Alireza Khodadadi-Jamayran, Celestia Fang, Julien Calvo, Blanca T. Gutierrez Diaz, Byoung-Kyu Cho, Valentina Serafin, Adam H. Lorch, Eric Wang, Cuijuan Han, and Yalu Zhou
Abstract: KEGG Enrichment Analysis of Differential Expressed Genes Between Thymus and T-ALL
Published: 2023

23. Pediatric Patient-Derived-Xenograft development in MAPPYACTS – international pediatric cancer precision medicine trial in relapsed and refractory tumors

Author: Maria Eugenia Marques da Costa, Sakina Zaidi, Jean-Yves Scoazec, Robin Droit, Wan Ching Lim, Antonin Marchais, Jérome Salmon, Sarah Cherkaoui, Raphael Morscher, Anouchka Laurent, Sébastien Malinge, Thomas Mercher, Séverine Tabone-Eglinger, Isabelle Goddard, Francoise Pflumio, Julien Calvo, Françoise Rédini, Natacha Entz-Werle, Aroa Soriano, Alberto Villanueva, Stefano Cairo, Pascal Chastagner, Massimo Moro, Cormac Owens, Michela Casanova, Raquel Hladun, Pablo Berlanga, Estelle Daudigeos-Dubus, Philippe Dessen, Laurence Zitvogel, Ludovic Lacroix, Gaelle Pierron, Olivier Delattre, Gudrun Schleiermacher, Didier Surdez, and Birgit Geoerger
Abstract: Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Paediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This new PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and new treatments development in advanced pediatric malignancies.
Published: 2023

24. Human hematopoietic stem/progenitor cells display reactive oxygen species-dependent long-term hematopoietic defects after exposure to low doses of ionizing radiations

Author: Vilma Barroca, Andreas Lefevre, Véronique Ménard, Marie-Laure Arcangeli, Elia Henry, Inès Souissi-Sahraoui, Françoise Pflumio, Anna Campalans, Julien Calvo, and Margaux Deynoux
Subjects: chemistry.chemical_classification, Reactive oxygen species, Cellular differentiation, medicine.medical_treatment, Hematopoietic Tissue, Hematology, Hematopoietic stem cell transplantation, Cell biology, Blood cell, Haematopoiesis, medicine.anatomical_structure, chemistry, medicine, Stem cell, Progenitor cell
Abstract: Hematopoietic stem cells are responsible for life-long blood cell production and are highly sensitive to exogenous stresses. The effects of low doses of ionizing radiations on radiosensitive tissues such as the hematopoietic tissue are still unknown despite their increasing use in medical imaging. Here, we study the consequences of low doses of ionizing radiations on differentiation and self-renewal capacities of human primary hematopoietic stem/progenitor cells (HSPC). We found that a single 20 mGy dose impairs the hematopoietic reconstitution potential of human HSPC but not their differentiation properties. In contrast to high irradiation doses, low doses of irradiation do not induce DNA double strand breaks in HSPC but, similar to high doses, induce a rapid and transient increase of reactive oxygen species (ROS) that promotes activation of the p38MAPK pathway. HSPC treatment with ROS scavengers or p38MAPK inhibitor prior exposure to 20 mGy irradiation abolishes the 20 mGy-induced defects indicating that ROS and p38MAPK pathways are transducers of low doses of radiation effects. Taken together, these results show that a 20 mGy dose of ionizing radiation reduces the reconstitution potential of HSPC suggesting an effect on the self-renewal potential of human hematopoietic stem cells and pinpointing ROS or the p38MAPK as therapeutic targets. Inhibition of ROS or the p38MAPK pathway protects human primary HSPC from low-dose irradiation toxicity.
Published: 2019

25. Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia

Author: Clément Bodineau, Benjamin Uzan, Sebastian van Liempd, Jean-Max Pasquet, Juan M. Falcón-Pérez, Elodie Muzotte, H. Rezvani, Julien Calvo, Elodie Richard, María L. Toribio, Patricia Fuentes, Isabelle Redonnet-Vernhet, Silvia Terés, Marion Bouchecareilh, Mercedes Tomé, Pierre Soubeyran, Piedad del Socorro Murdoch, Benoit Rousseau, Tra Ly Nguyen, Françoise Pflumio, Marie-Julie Nokin, Oriane Galmar, Raúl V. Durán, Abdel-Majid Khatib, Muriel Priault, Centre National de la Recherche Scientifique (CNRS), Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Agencia Estatal de Investigación (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Institut National de la Santé et de la Recherche Médicale (France), Ligue Nationale contre le Cancer (France), Université de Bordeaux, Fondation pour la Recherche Médicale, Conseil régional d'Aquitaine, Fondation ARC pour la Recherche sur le Cancer, Fonds de la Recherche Scientifique (Fédération Wallonie-Bruxelles), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), [Nguyen,TL, Nokin,MJ, Terés,S, Bodineau,C, Galmnar,O, Durán,RV] Institut Europeen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France. [Tomé,M, Murdoch,PDS, Durán,RV] Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Seville, Spain. [Tomé,M, Khatib,AM] Angiogenesis and Cancer Microenvironment Laboratory INSERM U1029, Universite de Bordeaux, Pessac, France. [Pasquet,JM, Muzotte,E, Rezvani,HR] INSERM, BMGIC, U1035, University of Bordeaux, France. [Rousseau,B] Service Commun des Animaleries, University of Bordeaux, France. [van Liempd,S, Falcon-Perez,JM] Exosomes Laboratory and Platform of Metabolomics, CIC bioGUNE, CIBERehd, Derio, Spain. [Falcon-Perez,JM] IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. [Richard,E] Institut Bergonie, INSERM U1218, University of Bordeaux, France. [Priault,M] Institut de Biochimie et Gen etique Cellulaires, CNRS UMR 5095, Université de Bordeaux, France. [Bouchecareilh,M] Bordeaux Research in Translational Oncology, INSERM U1053, Universite de Bordeaux, France. [Redonnet-Vernhet,I] Maladies Heréditaires du Métabolisme, Laboratoire de Biochimie, Hôpital Pellegrin, CHU Bordeaux, France. [Calvo,J, Uzan,B, Pflumio, F] UMR967, Inserm, CEA, Universite Paris 7, UniversitéParis 11, Fontenay-aux-Roses, France. [Fuentes,P, Toribio,ML] Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autonoma de Madrid, Spain. [Murdoch,PDS] Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, Spain, and This work was supported by funds from the following institutions: Agencia Estatal de Investigación/European Regional Development Fund, European Union (PGC2018-096244-B-I00, SAF2016-75442-R), Ministry of Science, Innovation and Universities of Spain, Spanish National Research Council—CSIC, Institut National de la Santé et de la Recherche Médicale—INSERM, Ligue Contre le Cancer—Gironde, Université de Bordeaux, Fondation pour la Recherche Médicale, the Conseil Régional d'Aquitaine, SIRIC-BRIO, Fondation ARC and Institut Européen de Chimie et Biologie. MJN was supported by a bourse d’excellence de la Fédération Wallonie-Bruxelles (WBI) and a postdoctoral fellowship from Fondation ARC. We thank Vincent Pitard (Flow Cytometry Platform, Université de Bordeaux, France) for technical assistance in flow cytometry experiments. We thank Diana Cabrera (Metabolomics Platform, CIC bioGUNE, Spain) for technical assistance in metabolomics analysis.
Subjects: 0301 basic medicine, Male, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], Cancer Research, Glutamina, Regulación hacia abajo, [SDV]Life Sciences [q-bio], Glutamine, mTORC1, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Diana mecanicista del complejo 1 de la rapamicina, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, Organisms::Eukaryota::Animals [Medical Subject Headings], Receptor, Notch1, Research Articles, RC254-282, ComputingMilieux_MISCELLANEOUS, Metabolismo, Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes [Medical Subject Headings], Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred NOD [Medical Subject Headings], Chemistry, Gene Expression Regulation, Leukemic, Línea celular, Metabolicaddiction, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, General Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 3. Good health, Leukemia, Oncology, 030220 oncology & carcinogenesis, embryonic structures, cardiovascular system, Molecular Medicine, biological phenomena, cell phenomena, and immunity, Glutamato-amoníaco ligasa, T-cell acute lymphoblastic leukemia, Research Article, Signal Transduction, Receptor Notch1, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Notch::Receptor, Notch1 [Medical Subject Headings], Down-Regulation, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic::Gene Expression Regulation, Leukemic [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mechanistic Target of Rapamycin Complex 1, Gene Expression Regulation, Enzymologic, Glutamine synthetase, 03 medical and health sciences, Downregulation and upregulation, Glutamate-Ammonia Ligase, Cell Line, Tumor, T‐cell acute lymphoblastic leukemia, Diseases::Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-Lymphoma [Medical Subject Headings], Genetics, medicine, Animals, Humans, Metabolic addiction, T-cell acutelymphoblastic leukemia, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Notch1, Glutaminolysis, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation [Medical Subject Headings], Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-Regulation [Medical Subject Headings], Cell growth, Leucemia-linfoma linfoblástico de células T precursoras, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Basic::Glutamine [Medical Subject Headings], medicine.disease, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Carbon-Nitrogen Ligases::Amide Synthases::Glutamate-Ammonia Ligase [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Enzymologic [Medical Subject Headings], 030104 developmental biology, Apoptosis, Downregulation, metabolic addiction, Cancer research, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Transgenic [Medical Subject Headings], sense organs, Cell line
Abstract: During glutamine sufficiency, both Notch‐positive and Notch‐negative T‐ALL cells promote glutamine catabolism, leading to mammalian target of rapamycin complex 1 (mTORC1) activation and cell growth and proliferation. However, during glutamine scarcity, only Notch‐negative T‐ALL cells can perform a metabolic adaptation by promoting glutamine synthesis. By contrast, Notch‐positive T‐ALL cells maintain glutamine catabolism during glutamine restriction, leading to glutamine addiction and mTORC1 dependency., The cellular receptor Notch1 is a central regulator of T‐cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T‐cell acute lymphoblastic leukemia (T‐ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T‐ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti‐Notch therapies in T‐ALL models. In this work, we report that Notch1 upregulation in T‐ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1‐driven T‐ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1‐induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1‐driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1‐driven leukemia.
Published: 2021

26. Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop

Author: Paola Ballerini, Frédéric Mazurier, Laurent Renou, Benjamin Uzan, Sara Chabi, Irina Naguibneva, André Baruchel, Lucine Fahy, Françoise Pflumio, Julien Calvo, Marie-Laure Arcangeli, Rima Haddad, Sandrine Poglio, Thierry Leblanc, Charly Le Maout, and Arnaud Petit
Subjects: Lymphoid Neoplasia, Cell growth, Chemistry, Hematology, mTORC1, Hypoxia (medical), Mitochondrion, Mechanistic Target of Rapamycin Complex 1, medicine.disease, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, medicine.anatomical_structure, Pharmaceutical Preparations, Drug Resistance, Neoplasm, medicine, Cancer research, Tumor Microenvironment, Humans, Glycolysis, Bone marrow, medicine.symptom, Hypoxia, PI3K/AKT/mTOR pathway
Abstract: Resistance to chemotherapy, a major therapeutic challenge in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), can be driven by interactions between leukemic cells and the microenvironment that promote survival of leukemic cells. The bone marrow, an important leukemia niche, has low oxygen partial pressures that highly participate in the regulation of normal hematopoiesis. Here we show that hypoxia inhibits T-ALL cell growth by slowing down cell cycle progression, decreasing mitochondria activity, and increasing glycolysis, making them less sensitive to antileukemic drugs and preserving their ability to initiate leukemia after treatment. Activation of the mammalian target of rapamycin (mTOR) was diminished in hypoxic leukemic cells, and treatment of T-ALL with the mTOR inhibitor rapamycin in normoxia mimicked the hypoxia effects, namely decreased cell growth and increased quiescence and drug resistance. Knocking down (KD) hypoxia-induced factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1α KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1α KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1α and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.
Published: 2020

27. Desperately seeking a home marrow niche for T-cell acute lymphoblastic leukaemia

Author: Julien Calvo, Lucine Fahy, Benjamin Uzan, Françoise Pflumio, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), CCSD, Accord Elsevier, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP)
Subjects: 0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Niche, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, Genetics, Hematologic malignancy, medicine, Tumor Microenvironment, Animals, Humans, Progenitor cell, Molecular Biology, Acute leukemia, business.industry, T-cell acute lymphoblastic leukaemia, medicine.disease, [SDV] Life Sciences [q-bio], Leukemia, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Hematopoietic progenitor cells, Bone marrow, business
Abstract: T-cell acute leukemia is a hematologic malignancy that results from the progressive acquisition of genomic abnormalities in T-cell progenitors/precursors. T-ALL is commonly thought to originate from the thymus albeit recent literature describes the possible acquisition of the first oncogenic hits in hematopoietic progenitor cells of the bone marrow (BM). The journey of T-ALL from its arising to full blown expansion meets different microenvironments, including the BM in which leukemic cells settle down early after the disease spreading. We take advantage of recent literature to give an overview of important cells and factors that participate in T-ALL, especially in the BM, arguing in favor of a home marrow niche for this rare leukemia.
Published: 2019

28. Speed of leukemia development and genetic diversity in xenograft models of T cell acute lymphoblastic leukemia

Author: André Baruchel, Judith Landman-Parker, Daniel Lewandowski, Paola Ballerini, Jean Soulier, Thierry Leblanc, Sandrine Poglio, Audrey Gros, Elodie Laharanne, Julien Calvo, Françoise Pflumio, Aurélie Caye, and Emmanuelle Clappier
Subjects: 0301 basic medicine, Human leukemia, Time Factors, T cell, Lymphoblastic Leukemia, Transplantation, Heterologous, Mice, Nude, Antigens, CD34, Mice, Transgenic, Mice, SCID, Newly diagnosed, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, clonal selection, Genetic Heterogeneity, Mice, Young Adult, 03 medical and health sciences, Mice, Inbred NOD, hemic and lymphatic diseases, Cell Line, Tumor, medicine, Animals, Humans, xenograft, Child, Translational oncology, business.industry, Genetic Variation, leukemia initiating cells, medicine.disease, Molecular biology, 3. Good health, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Oncology, Immunology, Disease Progression, Heterografts, Genetic selection, CD34, T-ALL, business, Neoplasm Transplantation, Research Paper
Abstract: // Sandrine Poglio 1, 2, 3, 4 , Daniel Lewandowski 2, 3, 4, 5 , Julien Calvo 1, 2, 3, 4 , Aurelie Caye 6, 7 , Audrey Gros 8, 9 , Elodie Laharanne 8, 9 , Thierry Leblanc 10 , Judith Landman-Parker 11 , Andre Baruchel 10 , Jean Soulier 6, 12, 13 , Paola Ballerini 1, 2, 3, 4, 11 , Emmanuelle Clappier 6, 12, 13 , Francoise Pflumio 1, 2, 3, 4 1 Commissariat a l’Energie Atomique et aux Energies Alternatives (CEA), DSV-IRCM-SCSR-LSHL, UMR 967, Fontenay-aux-Roses, France 2 INSERM, U967, Fontenay-aux-Roses, France 3 Universite Paris Diderot, Sorbonne Paris Cite, UMR 967, Fontenay-aux-Roses, France 4 Universite Paris-Sud, UMR 967, Fontenay-aux-Roses, France 5 CEA, DSV-IRCM-SCSR-LRTS, UMR 967, Fontenay-aux-Roses, France 6 Universite Paris Diderot, Paris, France 7 Assistance Publique-Hopitaux de Paris (AP-HP), Departement de Genetique, UF de Genetique Moleculaire, Hopital Robert Debre Paris, France 8 INSERM, UMR1053 Bordeaux Research in Translational Oncology (BaRITOn), Bordeaux, France 9 Universite de Bordeaux, Bordeaux, France 10 AP-HP, Service d’hematologie Pediatrique, Hopital Robert Debre, Paris, France 11 AP-HP, Service d’hematologie Pediatrique, Hopital Armand Trousseau, Paris, France 12 AP-HP, Laboratoire d’Hematologie, Hopital Saint-Louis, Paris, France 13 Team Genome and Cancer, U944 INSERM, Paris, France Correspondence to: Francoise Pflumio, email: francoise.pflumio@cea.fr Sandrine Poglio, email: sandrine.poglio@u-bordeaux.fr Keywords: T-ALL, leukemia initiating cells, clonal selection, CD34, xenograft Received: June 29, 2015 Accepted: April 22, 2016 Published: May 12, 2016 ABSTRACT T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7 + /CD34 + leukemic cell transplantations. Here we investigated the genetic characteristics of CD7 + /CD34 + and CD7 + /CD34 − cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7 + /CD34 + or CD7 + /CD34 − T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7 + /CD34 + or CD7 + /CD34 − cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments.
Published: 2016

29. Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

Author: María L. Toribio, José Luis Fuster, Clara Bueno, Julien Calvo, Francisco Gutierrez-Agüera, Jan Cools, Benjamin Uzan, Manuel Ramírez-Orellana, Françoise Pflumio, Sara González-García, Talia Velasco-Hernandez, Montserrat Torrebadell, Matteo Libero Baroni, O. Blanch-Lombarte, Pablo Menendez, Diego Sánchez-Martínez, Julia G. Prado, Jordi Juncà, Mireia Camós, and Heleia Roca-Ho
Subjects: Immunobiology and Immunotherapy, MONOCLONAL-ANTIBODY, T-Lymphocytes, medicine.medical_treatment, CD34, CHILDREN, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Biochemistry, Jurkat cells, Immunotherapy, Adoptive, Antigens, CD1, Jurkat Cells, Mice, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, CYTOGENETIC ABNORMALITIES, 0303 health sciences, Receptors, Chimeric Antigen, integumentary system, THYMECTOMY, SAFETY SWITCH, HUMAN THYMUS, Hematology, CHIMERIC ANTIGEN RECEPTOR, 3. Good health, medicine.anatomical_structure, IMMUNE FUNCTION, Life Sciences & Biomedicine, EXPRESSION, T cell, Immunology, MESENCHYMAL STEM-CELLS, 03 medical and health sciences, Antigen, Animals, Humans, Progenitor cell, 030304 developmental biology, Science & Technology, business.industry, Cell Biology, Immunotherapy, Xenograft Model Antitumor Assays, Chimeric antigen receptor, Cell culture, Drug Resistance, Neoplasm, Cancer research, business, Automobiles, 030215 immunology
Abstract: Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient-derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL. ispartof: BLOOD vol:133 issue:21 pages:2291-2304 ispartof: location:United States status: published
Published: 2018

30. Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells

Author: Stephen Taylor, Emmanouela Repapi, Catherine Porcher, Berthold Göttgens, Paresh Vyas, Dimitris Karamitros, Zahra Aboukhalil, Julien Calvo, Andreas Reinisch, Bilyana Stoilova, Françoise Pflumio, Marina Samitsch, Emmanuelle Six, Fiona K. Hamey, Lynn Quek, Jessica Doondeea, Nicolas Goardon, Ravindra Majeti, Batchimeg Usukhbayar, Georg W. Otto, The Weatherall Institute of Molecular Medicine, University of Oxford [Oxford], University of Cambridge [UK] (CAM), Stanford University School of Medicine [CA, USA], Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Cancer Biology and Genetics, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), University of Oxford, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Hamey, Fiona [0000-0001-7299-2860], Otto, Georg [0000-0002-3929-948X], Repapi, Emmanouela [0000-0001-8085-0731], Pflumio, Francoise [0000-0001-8995-596X], Vyas, Paresh [0000-0003-3931-0914], Apollo - University of Cambridge Repository, and Savelli, Bruno
Subjects: 0301 basic medicine, Myeloid, Cellular differentiation, [SDV]Life Sciences [q-bio], education, Immunology, Transplantation, Heterologous, Cell Separation, Biology, 03 medical and health sciences, Mice, medicine, Immunology and Allergy, Animals, Humans, Cell Lineage, Progenitor cell, health care economics and organizations, Cells, Cultured, Myeloid Progenitor Cells, Progenitor, Gene Expression Profiling, Hematopoietic Stem Cell Transplantation, Cell Differentiation, Lymphoid Progenitor Cells, Cell biology, 3. Good health, Hematopoiesis, [SDV] Life Sciences [q-bio], Transplantation, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Stem cell, Single-Cell Analysis
Abstract: International audience; The hierarchy of human hemopoietic progenitor cells that produce lymphoid and granulocytic–monocytic (myeloid) lineages is unclear. Multiple progenitor populations produce lymphoid and myeloid cells, but they remain incompletely characterized. Here we demonstrated that lympho-myeloid progenitor populations in cord blood — lymphoid-primed multi-potential progenitors (LMPPs), granulocyte-macrophage progenitors (GMPs) and multi-lymphoid progenitors (MLPs) — were functionally and transcriptionally distinct and heterogeneous at the clonal level, with progenitors of many different functional potentials present. Although most progenitors had the potential to develop into only one mature cell type (‘uni-lineage potential’), bi- and rarer multi-lineage progenitors were present among LMPPs, GMPs and MLPs. Those findings, coupled with single-cell expression analyses, suggest that a continuum of progenitors execute lymphoid and myeloid differentiation, rather than only uni-lineage progenitors’ being present downstream of stem cells.
Published: 2018

31. The SCL/TAL1 Transcription Factor Represses the Stress Protein DDiT4/REDD1 in Human Hematopoietic Stem/Progenitor Cells

Author: Marie-Laure Arcangeli, Maryam Mehrpour, Julien Calvo, Sophie Amsellem, Françoise Pflumio, Irina Naguibneva, Aissa Benyoucef, Anita van den Heuvel, Eric Soler, Jérôme Larghero, Laurent Renou, and Cell biology
Subjects: Transfection, Mice, Mice, Inbred NOD, Proto-Oncogene Proteins, Basic Helix-Loop-Helix Transcription Factors, T Cell Transcription Factor 1, Animals, Humans, Progenitor cell, Heat-Shock Proteins, T-Cell Acute Lymphocytic Leukemia Protein 1, PI3K/AKT/mTOR pathway, Gene knockdown, DDIT4, biology, Stem Cells, Intracellular Signaling Peptides and Proteins, Cell Biology, Hematopoietic Stem Cells, Haematopoiesis, biology.protein, Cancer research, Molecular Medicine, Stem cell, Chromatin immunoprecipitation, Transcription Factors, Developmental Biology, TAL1
Abstract: Hematopoietic stem/progenitor cells (HSPCs) are regulated through numerous molecular mechanisms that have not been interconnected. The transcription factor stem cell leukemia/T-cell acute leukemia 1 (TAL1) controls human HSPC but its mechanism of action is not clarified. In this study, we show that knockdown (KD) or short-term conditional over-expression (OE) of TAL1 in human HSPC ex vivo, respectively, blocks and maintains hematopoietic potentials, affecting proliferation of human HSPC. Comparative gene expression analyses of TAL1/KD and TAL1/OE human HSPC revealed modifications of cell cycle regulators as well as previously described TAL1 target genes. Interestingly an inverse correlation between TAL1 and DNA damage-induced transcript 4 (DDiT4/REDD1), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, is uncovered. Low phosphorylation levels of mTOR target proteins in TAL1/KD HSPC confirmed an interplay between mTOR pathway and TAL1 in correlation with TAL1-mediated effects of HSPC proliferation. Finally chromatin immunoprecipitation experiments performed in human HSPC showed that DDiT4 is a direct TAL1 target gene. Functional analyses showed that TAL1 represses DDiT4 expression in HSPCs. These results pinpoint DDiT4/REDD1 as a novel target gene regulated by TAL1 in human HSPC and establish for the first time a link between TAL1 and the mTOR pathway in human early hematopoietic cells. Stem Cells 2015;33:2268–2279
Published: 2015

32. DNMT3AR882H mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice

Author: Cécile K. Lopez, Kristian Helin, Elena Mylonas, Michaela Fontenay, Enguerran Mouly, Françoise Pflumio, P. Gaulard, Marianne Terndrup Pedersen, M'Boyba Diop, Michael Weber, Laurianne Scourzic, Lucile Couronné, Nathalie Droin, O. Bernard, Julien Calvo, Patrice Dubreuil, Ambre Bender, Philippe Dessen, N Martin, V Della Valle, Sylvain Guibert, Thomas Mercher, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Génétique des tumeurs ( U985 ), Institut Gustave Roussy ( IGR ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Norwegian Defence Intelligence School [Oslo] ( NDUC ), Centre de recherche en économie et management ( CREM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Centro de Aplicaciones de Tecnologías de Avanzada ( CENATAV ), CENATAV, Laboratoire Ligérien de Linguistique ( LLL ), Bibliothèque nationale de France ( BnF ) -Université d'Orléans ( UO ) -Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), The Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge [UK] ( CAM ), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Université Jean Monnet [Saint-Étienne] ( UJM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), and Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Cancer Research, Myeloid, Cellular differentiation, Notch signaling pathway, Biology, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, medicine.disease_cause, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, DNA Methyltransferase 3A, Dioxygenases, 03 medical and health sciences, Mice, Proto-Oncogene Proteins, medicine, Animals, Genes, Tumor Suppressor, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA (Cytosine-5-)-Methyltransferases, Mutation, Receptors, Notch, Myeloid leukemia, Cell Differentiation, Hematology, DNA Methylation, Lymphoproliferative Disorders, Transplantation, Gene expression profiling, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, Oncology, embryonic structures, DNA methylation, Immunology, Cancer research
Abstract: International audience; TEN-ELEVEN-TRANSLOCATION-2 (TET2) and DNA-METHYLTRANSFERASE-3A (DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2 and DNMT3A mutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2 inactivation and DNMT3A mutation affecting arginine 882 (DNMT3A(R882H)) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3A(R882H) Tet2(-/-) progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) Tet2(-/-) T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.
Published: 2016

33. Prevention of vaginal simian immunodeficiency virus transmission in macaques by postexposure prophylaxis with zidovudine, lamivudine and indinavir

Author: Patricia Brochard, Roger Le Grand, Henri Benech, Mirdad Kazanji, Sandrine Souquière, Nathalie Dereudre-Bosquet, Frédéric Martinon, Olivier Bourry, Maria Makuwa, and Julien Calvo
Subjects: genetic structures, Anti-HIV Agents, Injections, Subcutaneous, viruses, animal diseases, Immunology, Drug Evaluation, Preclinical, Simian Acquired Immunodeficiency Syndrome, Administration, Oral, Indinavir, Biology, medicine.disease_cause, Zidovudine, immune system diseases, Antiretroviral Therapy, Highly Active, medicine, Animals, Immunology and Allergy, Viremia, Sida, Reverse-transcriptase inhibitor, virus diseases, Lamivudine, Sexually Transmitted Diseases, Viral, Viral Load, Simian immunodeficiency virus, biology.organism_classification, Virology, CD4 Lymphocyte Count, Disease Models, Animal, Macaca fascicularis, Infectious Diseases, medicine.anatomical_structure, Vagina, Female, Viral load, medicine.drug
Abstract: To evaluate the efficacy of postexposure prophylaxis with a combination of zidovudine (ZDV), lamivudine (3TC) and indinavir (IDV), after vaginal exposure to HIV.: Experimental intravaginal exposure of female cynomolgus macaques to SIVmac251.ZDV/3TC/IDV treatment was initiated 4 h after exposure and continued for 28 days. Groups of six animals received a placebo or a combination of oral ZDV (4.5 mg/kg), 3TC (2.5 mg/kg) and IDV (20 mg/kg) twice daily or subcutaneous ZDV (4.5 mg/kg) and 3TC (2.5 mg/kg) twice daily, and a higher dose of IDV (60 mg/kg) administered orally twice daily.In the placebo group, all animals were infected. Antiretroviral association protected one of the six animals if all drugs were administered orally and four of the six animals if ZDV and 3TC were administered subcutaneously and IDV was given orally at triple dose. In infected animals, viremia was significantly delayed and lowered in treated animals than in animals given placebo, and high CD4 cell counts were maintained in the treated animals, at least in the medium term. Antiretroviral dosages made in macaques receiving the same treatments showed that protection efficacy could be linked to antiretroviral plasmatic concentration.This study shows, for the first time in macaques, that the postexposure prophylaxis recommended for humans may be effective after vaginal exposure. Improvements in pharmacokinetic parameters significantly increased treatment efficiency.
Published: 2009

34. CCR5 or CXCR4 use influences the relationship between CD4 cell depletion, NKp44L expression and NK cytotoxicity in SHIV-infected macaques

Author: Benoit Delache, Roger Le Grand, Frédéric Martinon, Hugues Fausther Bovendo, Vincent Vieillard, Julie Morin, Bruno Vaslin, Julien Calvo, Patrice Debré, Isabelle Picq, Patricia Brochard, and Raphaelle El Habib
Subjects: CD4-Positive T-Lymphocytes, Receptors, CXCR4, Receptors, CCR4, Receptors, CCR5, viruses, Amino Acid Motifs, Immunology, Simian Acquired Immunodeficiency Syndrome, Biology, Antibodies, Viral, medicine.disease_cause, CXCR4, Natural killer cell, medicine, Animals, Immunology and Allergy, Receptors, Immunologic, Cytotoxicity, Tropism, Natural Cytotoxicity Triggering Receptor 2, virus diseases, Simian immunodeficiency virus, Cytotoxicity Tests, Immunologic, Virology, HIV Envelope Protein gp41, CD4 Lymphocyte Count, Killer Cells, Natural, Macaca fascicularis, Cytolysis, Infectious Diseases, medicine.anatomical_structure, Tissue tropism, biology.protein, Simian Immunodeficiency Virus, Antibody, Reassortant Viruses
Abstract: Objective: HIV-1 infection is characterized by a progressive decline of CD4 cell count, the underlying mechanisms of which are still debated. We recently found that during HIV-1 infection, CD4 T cells overexpress a ligand of the NK activating receptor NKp44 (NKp44L) and are sensitized to NK cytolytic activity. The expression of NKp44L is triggered by a highly conserved motif of gp41 (3S) and is inhibited by anti-3S antibodies. Design: To assess whether viral tropism can affect NKp44L expression, NK cytotoxicity, and anti-3S antibodies production, 10 macaques were infected either with the CCR5 tropic SHIV 162P3 or with a CXCR4/CCR5 dual-tropic SHIV 89.6 P. Results: In SHlV 162P3 -infected macaques, expression of NKp44L was inversely correlated with anti-3S antibodies, in relation to CD4 depletion and NK cytotoxicity. By contrast, no such correlation was found in macaques infected with SHIV 89.6p which, induced a rapid decline of CD4 T cells. Conclusions: These results highlight the key role played by NK cells in CD4 cell count decline with respect to coreceptor usage, and provided the setting to investigate new strategies for preventive and/or therapeutic immunization to stimulate anti-3S antibodies.
Published: 2008

35. Dynamics of T-Cell Responses and Memory T Cells during Primary Simian Immunodeficiency Virus Infection in Cynomolgus Macaques

Author: Julien Calvo, Patricia Brochard, Bruno Vaslin, Roger Le Grand, Benoit Delache, Benoit Malleret, and Ingrid Karlsson
Subjects: CD4-Positive T-Lymphocytes, Male, Cellular immunity, T-Lymphocytes, animal diseases, viruses, T cell, Immunology, Simian Acquired Immunodeficiency Syndrome, CD8-Positive T-Lymphocytes, Lymphocyte Activation, medicine.disease_cause, Microbiology, Virus, Immune system, Virology, medicine, Animals, biology, T-Lymphocytes, Helper-Inducer, Viral Load, Simian immunodeficiency virus, biology.organism_classification, Macaca fascicularis, medicine.anatomical_structure, Insect Science, Lentivirus, Pathogenesis and Immunity, RNA, Viral, Simian Immunodeficiency Virus, Immunologic Memory, Viral load, CD8
Abstract: Cellular immune responses make an important contribution to both the control of human immunodeficiency virus (HIV) replication and disease progression. We used a pathogenic model of SIVmac251 infection of cynomolgus macaques to longitudinally evaluate cellular immune responses in association with various rates of disease progression. We found an inverse relationship between plasma viral load and the simian immunodeficiency virus (SIV)-specific T cells responses in peripheral blood and lymph nodes. SIV-specific T-cell responses in peripheral blood were transient during primary infection, with the highest responses detected around 3 months after infection. There was also a transient increase of central memory CD8 + T cells in peripheral blood during primary infection, and effector memory T-cell counts in peripheral lymph nodes were increased. This study emphasizes the importance of the early virus-specific immune responses in the outcome of HIV/SIV disease and provides details about the changes of virus-specific immune responses over time.
Published: 2007

36. FoxP3+CD25+CD8+T-Cell Induction during Primary Simian Immunodeficiency Virus Infection in Cynomolgus Macaques Correlates with Low CD4+T-Cell Activation and High Viral Load

Author: Benoit Delache, Bruno Vaslin, Julien Calvo, Ingrid Karlsson, Roger Le Grand, Patricia Brochard, and Benoit Malleret
Subjects: CD4-Positive T-Lymphocytes, Male, Immunology, Simian Acquired Immunodeficiency Syndrome, chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, Biology, Lymphocyte Activation, T-Lymphocytes, Regulatory, Microbiology, Interleukin 21, Immune system, Virology, Animals, Humans, Cytotoxic T cell, IL-2 receptor, Interleukin-2 Receptor alpha Subunit, FOXP3, hemic and immune systems, Forkhead Transcription Factors, Viral Load, Macaca fascicularis, Chronic infection, Insect Science, RNA, Viral, Pathogenesis and Immunity, Simian Immunodeficiency Virus, Immunologic Memory, Viral load, CD8
Abstract: The early immune response fails to prevent the establishment of chronic human immunodeficiency virus (HIV) infection but may influence viremia during primary infection, thereby possibly affecting long-term disease progression. CD25+FoxP3+regulatory T cells may contribute to HIV/simian immunodeficiency virus (SIV) pathogenesis by suppressing efficient antiviral responses during primary infection, favoring high levels of viral replication and the establishment of chronic infection. In contrast, they may decrease immune activation during chronic infection. CD4+regulatory T cells have been studied in the most detail, but CD8+CD25+FoxP3+T cells also have regulatory properties. We monitored the dynamics of CD25+FoxP3+T cells during primary and chronic SIVmac251 infection in cynomolgus macaques. The number of peripheral CD4+CD25+FoxP3+T cells paralleled that of memory CD4+T cells, with a rapid decline during primary infection followed by a rebound to levels just below baseline and gradual depletion during the course of infection. No change in the proportion of CD25+FoxP3+T cells was observed in peripheral lymph nodes. A small number of CD4+CD25+FoxP3+T cells at set point was associated with a high plasma viral load. In contrast, peripheral CD8+CD25+FoxP3+T cells were induced a few days after peak plasma viral load during primary infection. The number of these cells was positively correlated with viral load and negatively correlated with CD4+T-cell activation, SIV antigen-specific proliferative responses during primary infection, and plasma viral load at set point, with large numbers of CD8+CD25+FoxP3+T cells being indicative of a poor prognosis.
Published: 2007

37. Single cell assays unveil functional and transcriptional heterogeneity of human hemopoietic lympho-myeloid progenitors

Author: Jessica Doondeea, Andreas Reinisch, Zahra Aboukhalil, Fiona K. Hamey, Françoise Pflumio, Marina Samitsch, Georg W. Otto, Bilyana Stoilova, Berthold Göttgens, Lynn Quek, Ravindra Majeti, Emmanouela Repapi, Catherine Porcher, Julien Calvo, Paresh Vyas, Batchimeg Usukhbayar, Nicolas Goardon, Emmanuelle Six, Stephen S. Taylor, and Dimitris Karamitros
Subjects: Cancer Research, Haematopoiesis, Myeloid, medicine.anatomical_structure, Cell, Genetics, medicine, Cell Biology, Hematology, Biology, Progenitor cell, Molecular Biology, Cell biology
Published: 2017

38. Interleukin‐18 produced by bone marrow‐derived stromal cells supports T ‐cell acute leukaemia progression

Author: Paola Ballerini, Florence Armstrong, Françoise Pflumio, André Baruchel, Frederic Baleydier, Véronique Baud, Sandrine Poglio, Julia Gross, Thierry Leblanc, Julien Calvo, Diana Passaro, Judith Landman-Parker, Caroline Deswarte, Florent Dumont, Ching-Lien Wu, Xavier Cahu, Jacques Ghysdael, Corinne Besnard-Guerin, Bastien Gerby, Benjamin Uzan, Françoise Porteu, Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Jet Propulsion Laboratory (JPL), California Institute of Technology (CALTECH)-NASA, Service d'hématologie pédiatrique, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chimie Moléculaire (SCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Mobile Network Performance Group, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Inorganic Chemistry Laboratory [Oxford], University of Oxford, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Bos, Mireille, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), University of Oxford [Oxford], Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Clinique, Centre hospitalier universitaire de Nantes (CHU Nantes), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], NASA-California Institute of Technology (CALTECH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), CEA Direction des Sciences du Vivant (CEA/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Chimie Moléculaire ( SCM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), RWTH Aachen University [Aachen], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), and Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL )
Subjects: MAPK/ERK pathway, Stromal cell, MAP Kinase Signaling System, T-Lymphocytes, medicine.medical_treatment, T cell, [SDV]Life Sciences [q-bio], Bone Marrow Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, Cell Line, Tumor, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Research Articles, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, stromal cells, 0303 health sciences, Gene Expression Regulation, Leukemic, Cell growth, Interleukin-18, T-ALL Subject Categories Cancer, Cytokine, medicine.anatomical_structure, Cell culture, inflammation, 030220 oncology & carcinogenesis, Immunology, Cancer research, Molecular Medicine, Interleukin 18, Bone marrow, T-ALL, IL-18, Haematology
Abstract: International audience; Development of novel therapies is critical for T-cell acute leukae-mia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activa-tion and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/ 2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleu-kin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xeno-grafted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development.
Published: 2014

39. Antiretroviral treatment start-time during primary SIV(mac) infection in macaques exerts a different impact on early viral replication and dissemination

Author: Julien Calvo, Sophie Prevot, Patricia Brochard, Pierre Sellier, Pierre Roques, Olivier Bourry, Benoit Delache, Nathalie Dereuddre-Bosquet, and Abdelkrim Mannioui
Subjects: CD4-Positive T-Lymphocytes, Time Factors, Simian Acquired Immunodeficiency Syndrome, Public Health and Epidemiology/Infectious Diseases, Antigens, Differentiation, Myelomonocytic, lcsh:Medicine, Biology, CD8-Positive T-Lymphocytes, Placebo, Virus Replication, Peripheral blood mononuclear cell, Virus, Antigens, CD, Cell Movement, Antiretroviral Therapy, Highly Active, Blood plasma, Cytotoxic T cell, Animals, lcsh:Science, Multidisciplinary, lcsh:R, RNA, Infectious Diseases/HIV Infection and AIDS, Viral Load, Virology, Viral replication, Organ Specificity, Virology/Immunodeficiency Viruses, Immunology, Virology/Animal Models of Infection, Macaca, Simian Immunodeficiency Virus, lcsh:Q, Viral load, Research Article
Abstract: Background The time of infection is rarely known in human cases; thus, the effects of delaying the initiation of antiretroviral therapy (ART) on the peripheral viral load and the establishment of viral reservoirs are poorly understood. Methodology/Principal Findings Six groups of macaques, infected intravenously with SIVmac251, were given placebo or antiretroviral therapy to explore reservoir establishment; macaques were treated for 2 weeks, with treatment starting 4 hours, 7 or 14 days after infection. Viral replication and dissemination were measured in the gut (rectum), in the lung and in blood and lymphoid tissues (peripheral lymph nodes), by quantifying viral RNA, DNA and 2LTR circles. We used immunohistochemistry (CD4 and CD68) to assess the impact of these treatments on the relative amount of virus target cells in tissue. Treatment that was started 4 hours post-infection (pi) decreased viral replication and dissemination in blood and tissue samples, which were assessed on day 14 (RNA/DNA/2LTR circles). The virus remained detectable and lymphoid tissues were activated in LN and the gut in both placebo- and ART-treated animals. Viral RNA in plasma continued to be lower in macaques treated seven days after infection; however, this was not the case for viral DNA in peripheral blood mononuclear cells. There was a small but significant difference in RNA and DNA levels in tissues between placebo- and ART-treated animals on day 21. When started 14 days after infection, treatment resulted in a limited decrease in the plasma viral load. Conclusions Treatment that was started 4 hours after infection significantly reduced viral replication and dissemination. When started 7 days after infection, it was of slight virological benefit in peripheral blood and in tissues, and treatment was even less effective if started 14 days pi. These data favor starting ART no longer than one week after intravenous SIVmac251 exposure.
Published: 2010

40. NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity

Author: Judith Landman-Parker, Philippe Brunet de la Grange, Bastien Gerby, Paul-Henri Romeo, Nicolas Boissel, Michaela Fontenay, Françoise Pflumio, Julien Calvo, André Baruchel, Florence Armstrong, Paola Ballerini, Hervé Dombret, Marie-Christine Rouyez, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'hématologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Cellular immunity, Stromal cell, [SDV]Life Sciences [q-bio], Immunology, Notch signaling pathway, Regulator, Cell Culture Techniques, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, Mice, SCID, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Mice, Inbred NOD, Calcium-binding protein, Precursor cell, Tumor Cells, Cultured, Animals, Humans, Receptor, Notch1, Receptor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Cell growth, Calcium-Binding Proteins, Genes, T-Cell Receptor gamma, Membrane Proteins, Cell Biology, Hematology, Coculture Techniques, Cell biology, 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, Amyloid Precursor Protein Secretases, Stromal Cells, Oligopeptides, Neoplasm Transplantation, Signal Transduction
Abstract: Understanding the pathways that regulate the human T-cell acute lymphoblastic leukemia (T-ALL) initiating cells (T-LiC) activity has been hampered by the lack of biologic assays in which this human disease can be studied. Here we show that coculture of primary human T-ALL with a mouse stromal cell line expressing the NOTCH ligand delta-like-1 (DL1) reproducibly allowed maintenance of T-LiC and long-term growth of blast cells. Human T-ALL mutated or not on the NOTCH receptor required sustained activation of the NOTCH pathway via receptor/ligand interaction for growth and T-LiC activity. On the reverse, inhibition of the NOTCH pathway during primary cultures abolished in vitro cell growth and in vivo T-LiC activity. Altogether, these results demonstrate the major role of the NOTCH pathway activation in human T-ALL development and in the maintenance of leukemia-initiating cells.
Published: 2009

41. [Demonstration of leukemic stem cells in the human T-ALLs and study of the involvement of the NOTCH, TAL1 and ERK/MAPK pathways in human T-leukemogenesis]

Author: Bastien, Gerby, Florence, Armstrong, Philippe, Brunet de la Grange, Julien, Calvo, Paula, Ballerini, and Françoise, Pflumio
Subjects: Cell Transformation, Neoplastic, Receptors, Notch, MAP Kinase Signaling System, Proto-Oncogene Proteins, Basic Helix-Loop-Helix Transcription Factors, Neoplastic Stem Cells, Humans, Extracellular Signal-Regulated MAP Kinases, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, T-Cell Acute Lymphocytic Leukemia Protein 1, Neoplasm Proteins, Signal Transduction
Published: 2008

42. Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression

Author: Pierre Lebon, Thibault Andrieu, Patricia Brochard, Benjamin Manéglier, Ingrid Karlsson, Leïla Perié, Anne Hosmalin, Bruno Vaslin, Odile Spreux-Varoquaux, Roger Le Grand, Michelina Nascimbeni, Benoit Malleret, Benoit Delache, Julien Calvo, Service de virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunopathologie Expérimentale, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire d'Immuno-Pathologie Expérimentale, Service de Neurovirologie, Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CRSSA, Laboratoire de Neuro-Immuno-Virologie, Service de Neurovirologie EMI E-01 (UMR E01), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Saint-Vincent de Paul, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11) - École pratique des hautes études (EPHE) - Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - CRSSA, Université Paris-Sud - Paris 11 (UP11) - Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Saint-Vincent de Paul, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CRSSA, and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: CD4-Positive T-Lymphocytes, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Simian Acquired Immunodeficiency Syndrome, Plasmacytoid dendritic cell, Biology, CD8-Positive T-Lymphocytes, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cell Movement, medicine, Immune Tolerance, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Viremia, Antigen-presenting cell, Acute-Phase Reaction, 030304 developmental biology, 0303 health sciences, Interleukin-18, Interleukin-2 Receptor alpha Subunit, FOXP3, Cell Biology, Hematology, Dendritic cell, Dendritic Cells, Simian immunodeficiency virus, Acquired immune system, Virology, 3. Good health, Macaca fascicularis, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Simian Immunodeficiency Virus, Lymph Nodes, Interferon type I, 030215 immunology, medicine.drug
Abstract: Plasmacytoid dendritic cells (pDCs) are antigen-presenting cells that develop into type-I interferon (IFN-I)–producing cells in response to pathogens. Their role in human immunodeficiency virus (HIV) pathogenesis needs to be understood. We analyzed their dynamics in relation to innate and adaptive immunity very early during the acute phase of simian immunodeficiency virus (SIV) infection in 18 macaques. pDC counts decreased in blood and increased in peripheral lymph nodes, consistent with early recruitment in secondary lymphoid tissues. These changes correlated with the kinetic and intensity of viremia and were associated with a peak of plasma IFN-I. IFN-I and viremia were positively correlated with functional activity of the immune suppression associated enzyme indoleamine-2,3-dioxygenase (IDO) and FoxP3+CD8+ T cells, which both negatively correlated with SIV-specific T-cell proliferation and CD4+ T-cell activation. These data suggest that pDCs and IFN-I play a key role in shaping innate and adaptive immunity toward suppressive pathways during the acute phase of SIV/HIV primary infection.
Published: 2008

43. Declined Presentation

Author: Naïs Prade, Jacques Ghysdael, André Baruchel, Paola Ballerini, Frederic Baleydier, Judith Landman-Parker, Arnaud Petit, Xavier Cahu, Sandrine Poglio, Françoise Pflumio, Benjamin Uzan, Julien Calvo, Eric Delabesse, and Thierry Leblanc
Subjects: Cancer Research, T cell, Lymphoblastic Leukemia, Cell Biology, Hematology, Biology, medicine.anatomical_structure, Adipogenesis, Immunology, Genetics, medicine, Bone marrow, Presentation (obstetrics), Molecular Biology
Published: 2014

44. Mise en évidence des cellules souches leucémiques dans les LAL-T humaines et étude de l’implication des voies NOTCH, TAL1 et ERK/MAPK dans la leucémogenèse T humaine

Author: Florence Armstrong, Paula Ballerini, Françoise Pflumio, Bastien Gerby, Philippe Brunet de la Grange, Julien Calvo, Laboratoire des cellules souches hématopoïétiques et leucémiques (LGSC), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, [SDV]Life Sciences [q-bio], T-Cell Acute Lymphocytic Leukemia Protein 1, Notch signaling pathway, Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, T lymphocyte, Biology, medicine.disease, Molecular biology, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Acute lymphocytic leukemia, Mitogen-activated protein kinase, medicine, biology.protein, Signal transduction, Receptor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2008

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