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1. Anti-CD38 therapy impairs SARS-CoV-2 vaccine response against alpha and delta variants in patients with multiple myeloma

Author

Soledad Henriquez, Jérémie Zerbit, Timothée Bruel, Amani Ouedrani, Delphine Planas, Paul Deschamps, Isabelle Staropoli, Jérôme Hadjadj, Bruno Varet, Natalia Ermak, Didier Bouscary, Lise Willems, Guillemette Fouquet, Justine Decroocq, Patricia Franchi, Benedicte Deau-Fischer, Benjamin Terrier, Jérôme Tamburini, Lucienne Chatenoud, Olivier Schwartz, Marguerite Vignon, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Université de Genève (UNIGE), Université Paris Descartes - Paris 5 (UPD5), This study was supported by Fonds IMMUNOV for Innovation in Immunopathology, by the Institut Pasteur (for work in the OS laboratory), the Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale, and ANRS, and by grants from the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, and IDISCOVR. D.P. is supported by the Vaccine Research Institute., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute [Créteil, France] (VRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Université de Genève = University of Geneva (UNIGE)

Subjects
Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cell Biology, Hematology, Biochemistry, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2022
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2. Vasculitis associated with myelodysplastic syndrome and chronic myelomonocytic leukemia: French multicenter case-control study

Author

Jean-Sébastien Allain, Laure Swiader, Pierre Peterlin, Emmanuel Dao, Carole Philipponnet, Pierre Fenaux, Alexis Régent, Sylvain Thepot, Eric Solary, Philippe Guilpain, Benjamin Terrier, Noemie Jourde Chiche, Rolande Cohen-Valensi, Ygal Benhamou, On behalf Minhemon, Anne Laure Roupie, Jonathan Broner, Amadou Konate, Matthieu Wemeau, Guillaume Bussone, Matthieu Ponsoye, J. Galland, Aline Tanguy-Schmidt, Marielle Roux-Sauvat, Guilhem Cavaille, Xavier Puéchal, Olivier Fain, Azeddine Dellal, Nadia Baati, Hubert de Boysson, Maud D'Aveni, Vincent Jachiet, Aspasia Stamatoullas-Bastard, Constance Lahuna, Lionel Ades, Lenaig Le Clech, Arsène Mekinian, Alexis Guédon, Marc Lambert, Achille Aouba, Anne Parcelier, Sélim Corm, J. Seguier, Snfmi., Mathilde Versini, Emmanuel Ledoult, Matthieu Groh, Marc Ruivard, Fabrice Carrat, Benoit de Renzis, Julien Rossignol, Lise Willems, François Maurier, Anne Marfaing Koka, Nicolas Schleinitz, Viviane Queyrel, Cristina Belizna, Valérie Noc, Andrei Tchirkov, Louis Terriou, Grégoire Martin de Frémont, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Giant Cell Arteritis, Chronic myelomonocytic leukemia, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Rheumatology, hemic and lymphatic diseases, Internal medicine, Medicine, Humans, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, 030203 arthritis & rheumatology, Aged, 80 and over, Acute leukemia, business.industry, Polyarteritis nodosa, Case-control study, Leukemia, Myelomonocytic, Chronic, Odds ratio, Middle Aged, medicine.disease, 3. Good health, Giant cell arteritis, Anesthesiology and Pain Medicine, International Prognostic Scoring System, Case-Control Studies, Myelodysplastic Syndromes, Female, business, Vasculitis
Abstract

Introduction Our objective was to evaluate characteristics, treatment and outcome of vasculitis associated with myelodysplastic syndrome (MDS) and chronic myelomonicytic leukemia (CMML) Patients and Methods Retrospective descriptive analysis of MDS/CMML-related vasculitis and comparison with MDS/CMML patients without dysimmune features. Results Seventy patients with vasculitis and MDS/CMML were included, with median age of 71.5 [21–90] years and male/female ratio of 2.3. Vasculitis was diagnosed prior to MDS/CMML in 31 patients (44%), and after in 20 patients. In comparison with MDS/CMML without autoimmune/inflammatory features, vasculitis with MDS/MPN showed no difference in MDS/CMML subtypes distribution nor International Prognostic Scoring System and CMML-specific prognostic (IPSS/CPSS) scores. Vasculitis subtypes included Giant cell arteritis in 24 patients (34%), Behcet's-like syndrome in 11 patients (20%) and polyarteritis nodosa in 6 patients (9%). Glucocorticoids (GCs) were used as first-line therapy for MDS/CMML vasculitis in 64/70 patients (91%) and 41 (59%) received combined immunosuppressive therapies during the follow-up. After a median follow-up of 33.2 months [1–162], 31 patients (44%) achieved sustained remission. At least one relapse occurred in 43 patients (61%). Relapse rates were higher in patients treated with conventional Disease Modifying Anti-Rheumatic Drug (DMARDs) (odds ratio 4.86 [95% CI 1.38 - 17.10]), but did not differ for biologics (odds ratio 0.59 [95% CI 0.11–3.20]) and azacytidine (odds ratio 1.44 [95% CI 0.21–9.76]) than under glucocorticoids. Overall survival in MDS/CMML vasculitis was not significantly different from MDS/CMML patients without autoimmune/inflammatory features (p = 0.5), but acute leukemia progression rates were decreased (log rank Conclusion This study shows no correlation of vasculitis diagnoses with subtypes and severity of MDS/CMML, and no significant impact of vasculitis on overall survival. Whereas conventional DMARDs seem to be less effective, biologics or azacytidine therapy could be considered for even low-risk MDS/CMML vasculitis.

Published
2020
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3. Giant-cell arteritis associated with myelodysplastic syndrome: French multicenter case control study and literature review

Author

Julien Rossignol, Hubert de Boysson, Anne Laure Roupie, Viviane Queyrel, Maud d'Aveni, Azeddine Dellal, Mathilde Versini, Eric Solary, François Maurier, Nicolas Schleinitz, J. Galland, Sara Thietart, J. Seguier, Olivier Decaux, Ygal Benhamou, Louis Terriou, Achille Aouba, Fabrice Carrat, Lise Willems, on behalf Minhemon, Maxime Samson, Arsène Mekinian, Pierre Fenaux, Olivier Fain, Matthieu Groh, Lionel Ades, Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de médecine interne [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Marseille, Service de médecine interne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Foch [Suresnes], Service de Médecine Interne [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpitaux Privés de Metz (HPMetz), Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hémato-oncologie [CHU Saint-Louis], 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), Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Service de Médecine Interne (SOC 1 et SOC 2) [CHU de Dijon], and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Immunology, Giant Cell Arteritis, Chronic myelomonocytic leukemia, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, Internal medicine, medicine, Immunology and Allergy, Humans, cardiovascular diseases, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, 030203 arthritis & rheumatology, Aged, 80 and over, business.industry, Incidence (epidemiology), Myelodysplastic syndromes, Case-control study, food and beverages, Middle Aged, medicine.disease, Myelodysplastic-Myeloproliferative Diseases, 3. Good health, Jaw claudication, Giant cell arteritis, 030104 developmental biology, Treatment Outcome, Myelodysplastic Syndromes, cardiovascular system, Anterior ischemic optic neuropathy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Headaches, medicine.symptom, business
Abstract

Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MDS/MPN) can be associated with giant cell arteritis (GCA). In this nationwide study by the "French Network of dysimmune disorders associated with hemopathies" (MINHEMON) the objective was to evaluate characteristics, treatment and outcome of GCA MDS-MDS/MPN.Retrospective analysis of patients that presented a MDS or MDS/MPN associated with GCA. Treatment efficiency, relapse-free and overall survival of GCA MDS-MDS/MPN were compared to GCA alone.Twenty-one patients with GCA MDS-MDS/MPN were included with median age 76 [42-92], M/F ratio 2.5, 8 MDS with multilineage dysplasia (38%), 4 chronic myelomonocytic leukemia (19%), at low or intermediate risk according to IPPS and IPSS-R. The prevalence of headaches, jaw claudication and anterior ischemic optic neuropathy was significantly lower in patients with GCA MDS-MDS/MPN compared to idiopathic GCA (14.3%, 0% and 0% versus 30%, 25%, and 25%, respectively; p .05). Other clinical and histology findings were similar. All GCA patients received steroid therapy as first-line treatment. Complete or partial response was observed in 14 GCA MDS-MDS/MPN patients (66.7%), of whom 6 (28.6%) received combined immunosuppressive therapies (versus 10% of idiopathic GCA; p = .07). Relapse incidence was similar in the two groups. Steroid dependence was more frequent among GCA MDS-MDS/MPN patients (12 (57%) versus 18 (22.5%); p .05). Relapse-free and steroid-free survivals were significantly decreased in GCA MDS-MDS/MPN patients (log rank 0.002 and 0.049 respectively), but not overall survival.Characteristics of GCA MDS-MDS/MPN seem different than idiopathic GCA, with a distinct clinical phenotype and poorer outcome with a higher risk of steroid dependence and relapse.

Published
2020
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4. Phenotypic landscape of granulocytes and monocytes by multiparametric flow cytometry: A prospective study of a 1-tube panel strategy for diagnosis and prognosis of patients with MDS

Author

Didier Bouscary, Charles Dussiau, Sylvain Barreau, Alexa S. Green, Valérie Bardet, Lise Willems, Nicolas Chapuis, Stephanie Mathis, Michaela Fontenay, Anna Raimbault, Anne-Sophie Alary, Olivier Kosmider, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), and The authors would like to thank Catherine Gicquel, Laurence Marnet, Bruno Montout, and Loetitia Rhino from the flow cytometry department (Assistance Publique-H?pitaux de Paris, H?pitaux Universitaires Paris Centre, Service d'H?matologie Biologique, Paris, France) for technical assistance and Dr. Isabelle Radford-Weiss and Dr. Sophie Kaltenbach (Assistance Publique-H?pitaux de Paris, H?pital Necker-Enfants maladies, Service d'Histologie-Embryologie-Cytog?n?tique, Paris, France) for cytogenetic analysis of MDS samples.

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Histology, Scoring system, diagnosis, [SDV]Life Sciences [q-bio], Monocytes, Pathology and Forensic Medicine, Flow cytometry, 03 medical and health sciences, Leukocyte Count, maturation pathways, 0302 clinical medicine, disease progression, hemic and lymphatic diseases, Internal medicine, medicine, MDS, Humans, Prospective Studies, Prospective cohort study, Aged, Aged, 80 and over, Cytopenia, medicine.diagnostic_test, business.industry, Myelodysplastic syndromes, Cell Biology, Middle Aged, medicine.disease, Flow Cytometry, Prognosis, Phenotype, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, multiparametric flow cytometry, Cohort, Reference database, Female, business, Granulocytes
Abstract

International audience; Background: Multiparametric flow cytometry (MFC) was recently reported to be a helpful additional tool in the diagnosis of myelodysplastic syndromes (MDS). However, numerous aberrancies have been reported that makes their evaluation difficult as part of a routine diagnosis. Methods: Here, we validated a 1-tube panel for the evaluation of granulocytic and monocytic maturation by MFC and correlated our findings with diagnosis and prognosis of MDS. A total of 251 samples with MDS suspicion were prospectively analyzed and compared to an internal reference database leading to the calculation of the Diff score. Results: The associated specificity and sensitivity values of this scoring system were 92.1% and 60.4% in a first learning cohort and 96.7% and 65.2% in a second independent validation cohort. The combination of the Diff score with the concomitantly calculated Ogata score increased the sensitivity to 74.2% and 78.3% in the learning and validation cohorts, respectively. Finally, a normal Diff score in MDS patients was associated with a significant prolonged progression-free survival. Conclusions: Taken together, the present data indicate that our strategy is a sensitive and specific MFC tool for the diagnosis of MDS-related cytopenia(s) which could be also useful for predicting evolution of these diseases.

Published
2020
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5. Improvement of therapy-induced myelodysplastic syndrome by infusion of autologous CD34-positive hematopoietic progenitor cells without chemotherapy

Author

Nicolas Chapuis, Raphael Carapito, Seiamak Bahram, Farhad Heshmati, Lise Willems, Isabelle Radford-Weiss, Marguerite Vignon, Olivier Kosmider, Jerome Tamburini, Didier Bouscary, Wendy Cuccuini, Alexa Green, Anne-Sophie Alary, Arash Rafii, Najeeb Halabi, Sophie Kaltenbach, Immuno-Rhumatologie Moléculaire, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)

Subjects
Oncology, Melphalan, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, CD34, Antigens, CD34, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematopoietic stem cell transplantation, Transplantation, Autologous, 03 medical and health sciences, 0302 clinical medicine, Antigen, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Multiple myeloma, Chemotherapy, business.industry, Hematopoietic Stem Cell Transplantation, Hematology, medicine.disease, Hematopoietic Stem Cells, 3. Good health, Transplantation, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Hematopoietic progenitor cells, business, 030215 immunology, medicine.drug
Abstract

Recent years have witnessed a dramatic improvement in multiple myeloma (MM) patient care with a current median life expectancy of 6 to 10 years dependent on age. High-dose melphalan followed by aut...

Published
2020
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6. Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study

Author

Vincent Levy, Marie-Sarah Dilhuydy, Gregory Lazarian, Anne Quinquenel, Rémi Letestu, Carole Fleury, Delphine Nollet, Florence Cymbalista, Luc-Matthieu Fornecker, Damien Roos-Weil, Alain Delmer, Katia Hormigos, Lise Willems, Romain Guieze, Anne-Sophie Michallet, Loic Ysebaert, Pierre Feugier, Fanny Baran-Marszak, Centre Hospitalier Universitaire de Reims (CHU Reims), Université de Reims Champagne-Ardenne (URCA), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Les Hôpitaux Universitaires de Strasbourg (HUS), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Groupe Hospitalier Universitaire Paris Seine-Saint-Denis (GHUPSSD), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Sorbonne Paris Nord, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Universités (COMUE), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Léon Bérard [Lyon], Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté des Sciences Fondamentales et Biomédicales (UPD5 Sciences), Université Paris Descartes - Paris 5 (UPD5), CHADEYRON, DOMINIQUE, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
Oncology, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Lymphocytosis, Chronic lymphocytic leukemia, Immunology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, Bruton's tyrosine kinase, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, medicine.disease, 3. Good health, Leukemia, chemistry, Specimen collection, 030220 oncology & carcinogenesis, Ibrutinib, Cohort, biology.protein, Sample collection, medicine.symptom, business
Abstract

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a “snapshot” of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.

Published
2019
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7. IκB kinase overcomes PI3K/Akt and ERK/MAPK to control FOXO3a activity in acute myeloid leukemia

Author

Catherine Lacombe, Alexa S. Green, Valérie Bardet, Didier Bouscary, Frédérique Verdier, Norbert Ifrah, Georges Bismuth, Nicolas Chapuis, Laurent Leotoing, Patrick Mayeux, Fabrice Agou, Véronique Baud, François Dreyfus, Sophie Park, Jerome Tamburini, Lise Willems, Institut Cochin (IC 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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang, GOELAMS, Institut Pasteur [Paris] (IP), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), This work was supported by grants from the Ligue Nationale Contre le Cancer (LNCC, comité de paris), the Institut National du Cancer (INCa), the Fondation de France, and the Association Laurette Fugain. N.C. is recipient of a grant from Inserm, and J.T. and A.G. are recipients of grants from the Fondation pour la Recherche Medicale (FRM) and S.P. from the Assistance Publique des Hôpitaux de Paris/La Caisse Nationale d'Assurance Maladie (APHP/CANAM). V.B. is supported by the Agence Nationale pour la Recherche, Association pour la Recherche sur le Cancer, Belgian InterUniversity Attraction Pole, Cancéropole Ile-de-France, Institut National du Cancer, and Université Paris Descartes., Institut Pasteur [Paris], and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV]Life Sciences [q-bio], Apoptosis, IκB kinase, Biochemistry, Phosphatidylinositol 3-Kinases, MESH: Mutant Proteins, 0302 clinical medicine, MESH: Structure-Activity Relationship, Serine, MESH: Protein Kinase Inhibitors, Extracellular Signal-Regulated MAP Kinases, MESH: Extracellular Signal-Regulated MAP Kinases, 0303 health sciences, Kinase, Forkhead Box Protein O3, Myeloid leukemia, Forkhead Transcription Factors, Hematology, I-kappa B Kinase, Leukemia, Myeloid, Acute, Protein Transport, 030220 oncology & carcinogenesis, Mitogen-activated protein kinase, Signal transduction, MESH: Leukemia, Myeloid, Acute, MESH: Cell Nucleus, MESH: Protein Transport, MAP Kinase Signaling System, Recombinant Fusion Proteins, Immunology, Green Fluorescent Proteins, Biology, MESH: Forkhead Box Protein O3, 03 medical and health sciences, Structure-Activity Relationship, MESH: Green Fluorescent Proteins, MESH: Forkhead Transcription Factors, MESH: Cell Proliferation, MESH: Recombinant Fusion Proteins, Humans, MESH: Serine, MESH: I-kappa B Kinase, Protein kinase B, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, 030304 developmental biology, Cell Proliferation, Cell Nucleus, Phosphoinositide 3-kinase, MESH: Humans, MESH: MAP Kinase Signaling System, MESH: Proto-Oncogene Proteins c-akt, MESH: Apoptosis, Cell Biology, MESH: Phosphatidylinositol 3-Kinases, Cancer research, biology.protein, Mutant Proteins, Proto-Oncogene Proteins c-akt
Abstract

The FOXO transcription factors are involved in multiple signaling pathways and have tumor-suppressor functions. In acute myeloid leukemia (AML), deregulation of oncogenic kinases, including Akt, extra-signal–regulated kinase, or IκB kinase, is frequently observed, which may potentially inactivate FOXO activity. We therefore investigated the mechanism underlying the regulation of FOXO3a, the only FOXO protein constantly expressed in AML blast cells. We show that in both primary AML samples and in a MV4-11/FOXO3a-GFP cell line, FOXO3a is in a constant inactive state due to its cytoplasmic localization, and that neither PI3K/Akt nor extra-signal–regulated kinase–specific inhibition resulted in its nuclear translocation. In contrast, the anti-Nemo peptide that specifically inhibits IKK activity was found to induce FOXO3a nuclear localization in leukemic cells. Furthermore, an IKK-insensitive FOXO3a protein mutated at S644 translocated into the nucleus and activated the transcription of the Fas-L and p21Cip1 genes. This, in turn, inhibited leukemic cell proliferation and induced apoptosis. These results thus indicate that IKK activity maintains FOXO3a in the cytoplasm and establishes an important role of FOXO3a inactivation in the proliferation and survival of AML cells. The restoration of FOXO3a activity by interacting with its subcellular distribution may thus represent a new attractive therapeutic strategy for AML.

Published
2010
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