In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia

Autores
Vereertbrugghen, Alexia; Colado, Ana; Gargiulo, Ernesto; Bezares, Raimundo Fernando; Fernández Grecco, Horacio; Cordini, Gregorio; Custidiano, Maria del Rosario; François, Jean Hugues; Berchem, Guy; Borge, Mercedes; Paggetti, Jerome; Moussay, Etienne; Gamberale, Romina; Giordano, Mirta Nilda; Morande, Pablo Elías
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Current standard treatment of patients with hairy cell leukemia (HCL), a chronic B-cell neoplasia of low incidence that affects the elderly, is based on the administration of purine analogs such as cladribine. This chemotherapy approach shows satisfactory responses, but the disease relapses, often repeatedly. Venetoclax (ABT-199) is a Bcl-2 inhibitor currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in adult patients ineligible for intensive chemotherapy. Given that HCL cells express Bcl-2, our aim was to evaluate venetoclax as a potential therapy for HCL. We found that clinically relevant concentrations of venetoclax (0.1 and 1 µM) induced primary HCL cell apoptosis in vitro as measured by flow cytometry using Annexin V staining. As microenvironment induces resistance to venetoclax in CLL, we also evaluated its effect in HCL by testing the following stimuli: activated T lymphocytes, stromal cells, TLR-9 agonist CpG, and TLR-2 agonist PAM3. We found decreased levels of venetoclax-induced cytotoxicity in HCL cells exposed for 48 h to any of these stimuli, suggesting that leukemic B cells from HCL patients are sensitive to venetoclax, but this sensitivity can be overcome by signals from the microenvironment. We propose that the combination of venetoclax with drugs that target the microenvironment might improve its efficacy in HCL.
Fil: Vereertbrugghen, Alexia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Colado, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Gargiulo, Ernesto. Luxembourg Institute Of Health; Luxemburgo
Fil: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; Argentina
Fil: Fernández Grecco, Horacio. Sanatorio Municipal Dr. Julio Méndez; Argentina
Fil: Cordini, Gregorio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Custidiano, Maria del Rosario. Instituto Alexander Fleming; Argentina
Fil: François, Jean Hugues. Centre Hospitalier de Luxembourg; Luxemburgo
Fil: Berchem, Guy. Centre Hospitalier de Luxembourg; Luxemburgo. Luxembourg Institute of Health; Luxemburgo
Fil: Borge, Mercedes. Centre Hospitalier de Luxembourg; Luxemburgo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Paggetti, Jerome. Luxembourg Institute of Health; Luxemburgo
Fil: Moussay, Etienne. Luxembourg Institute of Health; Luxemburgo
Fil: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
Fil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
Fil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Luxembourg Institute of Health; Luxemburgo
Materia
ABT-199
CELL DEATH
HAIRY CELL LEUKEMIA
LEUKEMIA MICROENVIRONMENT
VENETOCLAX
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/212135
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell LeukemiaVereertbrugghen, AlexiaColado, AnaGargiulo, ErnestoBezares, Raimundo FernandoFernández Grecco, HoracioCordini, GregorioCustidiano, Maria del RosarioFrançois, Jean HuguesBerchem, GuyBorge, MercedesPaggetti, JeromeMoussay, EtienneGamberale, RominaGiordano, Mirta NildaMorande, Pablo ElíasABT-199CELL DEATHHAIRY CELL LEUKEMIALEUKEMIA MICROENVIRONMENTVENETOCLAXhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Current standard treatment of patients with hairy cell leukemia (HCL), a chronic B-cell neoplasia of low incidence that affects the elderly, is based on the administration of purine analogs such as cladribine. This chemotherapy approach shows satisfactory responses, but the disease relapses, often repeatedly. Venetoclax (ABT-199) is a Bcl-2 inhibitor currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in adult patients ineligible for intensive chemotherapy. Given that HCL cells express Bcl-2, our aim was to evaluate venetoclax as a potential therapy for HCL. We found that clinically relevant concentrations of venetoclax (0.1 and 1 µM) induced primary HCL cell apoptosis in vitro as measured by flow cytometry using Annexin V staining. As microenvironment induces resistance to venetoclax in CLL, we also evaluated its effect in HCL by testing the following stimuli: activated T lymphocytes, stromal cells, TLR-9 agonist CpG, and TLR-2 agonist PAM3. We found decreased levels of venetoclax-induced cytotoxicity in HCL cells exposed for 48 h to any of these stimuli, suggesting that leukemic B cells from HCL patients are sensitive to venetoclax, but this sensitivity can be overcome by signals from the microenvironment. We propose that the combination of venetoclax with drugs that target the microenvironment might improve its efficacy in HCL.Fil: Vereertbrugghen, Alexia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Colado, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gargiulo, Ernesto. Luxembourg Institute Of Health; LuxemburgoFil: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Fernández Grecco, Horacio. Sanatorio Municipal Dr. Julio Méndez; ArgentinaFil: Cordini, Gregorio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Custidiano, Maria del Rosario. Instituto Alexander Fleming; ArgentinaFil: François, Jean Hugues. Centre Hospitalier de Luxembourg; LuxemburgoFil: Berchem, Guy. Centre Hospitalier de Luxembourg; Luxemburgo. Luxembourg Institute of Health; LuxemburgoFil: Borge, Mercedes. Centre Hospitalier de Luxembourg; Luxemburgo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Paggetti, Jerome. Luxembourg Institute of Health; LuxemburgoFil: Moussay, Etienne. Luxembourg Institute of Health; LuxemburgoFil: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; ArgentinaFil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Luxembourg Institute of Health; LuxemburgoFrontiers Media2021-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/212135Vereertbrugghen, Alexia; Colado, Ana; Gargiulo, Ernesto; Bezares, Raimundo Fernando; Fernández Grecco, Horacio; et al.; In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia; Frontiers Media; Frontiers in Oncology; 11; 598319; 7-2021; 1-72234-943XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.598319/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fonc.2021.598319info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:13:30Zoai:ri.conicet.gov.ar:11336/212135instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:13:30.624CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia
title In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia
spellingShingle In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia
Vereertbrugghen, Alexia
ABT-199
CELL DEATH
HAIRY CELL LEUKEMIA
LEUKEMIA MICROENVIRONMENT
VENETOCLAX
title_short In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia
title_full In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia
title_fullStr In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia
title_full_unstemmed In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia
title_sort In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia
dc.creator.none.fl_str_mv Vereertbrugghen, Alexia
Colado, Ana
Gargiulo, Ernesto
Bezares, Raimundo Fernando
Fernández Grecco, Horacio
Cordini, Gregorio
Custidiano, Maria del Rosario
François, Jean Hugues
Berchem, Guy
Borge, Mercedes
Paggetti, Jerome
Moussay, Etienne
Gamberale, Romina
Giordano, Mirta Nilda
Morande, Pablo Elías
author Vereertbrugghen, Alexia
author_facet Vereertbrugghen, Alexia
Colado, Ana
Gargiulo, Ernesto
Bezares, Raimundo Fernando
Fernández Grecco, Horacio
Cordini, Gregorio
Custidiano, Maria del Rosario
François, Jean Hugues
Berchem, Guy
Borge, Mercedes
Paggetti, Jerome
Moussay, Etienne
Gamberale, Romina
Giordano, Mirta Nilda
Morande, Pablo Elías
author_role author
author2 Colado, Ana
Gargiulo, Ernesto
Bezares, Raimundo Fernando
Fernández Grecco, Horacio
Cordini, Gregorio
Custidiano, Maria del Rosario
François, Jean Hugues
Berchem, Guy
Borge, Mercedes
Paggetti, Jerome
Moussay, Etienne
Gamberale, Romina
Giordano, Mirta Nilda
Morande, Pablo Elías
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ABT-199
CELL DEATH
HAIRY CELL LEUKEMIA
LEUKEMIA MICROENVIRONMENT
VENETOCLAX
topic ABT-199
CELL DEATH
HAIRY CELL LEUKEMIA
LEUKEMIA MICROENVIRONMENT
VENETOCLAX
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Current standard treatment of patients with hairy cell leukemia (HCL), a chronic B-cell neoplasia of low incidence that affects the elderly, is based on the administration of purine analogs such as cladribine. This chemotherapy approach shows satisfactory responses, but the disease relapses, often repeatedly. Venetoclax (ABT-199) is a Bcl-2 inhibitor currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in adult patients ineligible for intensive chemotherapy. Given that HCL cells express Bcl-2, our aim was to evaluate venetoclax as a potential therapy for HCL. We found that clinically relevant concentrations of venetoclax (0.1 and 1 µM) induced primary HCL cell apoptosis in vitro as measured by flow cytometry using Annexin V staining. As microenvironment induces resistance to venetoclax in CLL, we also evaluated its effect in HCL by testing the following stimuli: activated T lymphocytes, stromal cells, TLR-9 agonist CpG, and TLR-2 agonist PAM3. We found decreased levels of venetoclax-induced cytotoxicity in HCL cells exposed for 48 h to any of these stimuli, suggesting that leukemic B cells from HCL patients are sensitive to venetoclax, but this sensitivity can be overcome by signals from the microenvironment. We propose that the combination of venetoclax with drugs that target the microenvironment might improve its efficacy in HCL.
Fil: Vereertbrugghen, Alexia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Colado, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Gargiulo, Ernesto. Luxembourg Institute Of Health; Luxemburgo
Fil: Bezares, Raimundo Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; Argentina
Fil: Fernández Grecco, Horacio. Sanatorio Municipal Dr. Julio Méndez; Argentina
Fil: Cordini, Gregorio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Custidiano, Maria del Rosario. Instituto Alexander Fleming; Argentina
Fil: François, Jean Hugues. Centre Hospitalier de Luxembourg; Luxemburgo
Fil: Berchem, Guy. Centre Hospitalier de Luxembourg; Luxemburgo. Luxembourg Institute of Health; Luxemburgo
Fil: Borge, Mercedes. Centre Hospitalier de Luxembourg; Luxemburgo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Paggetti, Jerome. Luxembourg Institute of Health; Luxemburgo
Fil: Moussay, Etienne. Luxembourg Institute of Health; Luxemburgo
Fil: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
Fil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
Fil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Luxembourg Institute of Health; Luxemburgo
description Current standard treatment of patients with hairy cell leukemia (HCL), a chronic B-cell neoplasia of low incidence that affects the elderly, is based on the administration of purine analogs such as cladribine. This chemotherapy approach shows satisfactory responses, but the disease relapses, often repeatedly. Venetoclax (ABT-199) is a Bcl-2 inhibitor currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in adult patients ineligible for intensive chemotherapy. Given that HCL cells express Bcl-2, our aim was to evaluate venetoclax as a potential therapy for HCL. We found that clinically relevant concentrations of venetoclax (0.1 and 1 µM) induced primary HCL cell apoptosis in vitro as measured by flow cytometry using Annexin V staining. As microenvironment induces resistance to venetoclax in CLL, we also evaluated its effect in HCL by testing the following stimuli: activated T lymphocytes, stromal cells, TLR-9 agonist CpG, and TLR-2 agonist PAM3. We found decreased levels of venetoclax-induced cytotoxicity in HCL cells exposed for 48 h to any of these stimuli, suggesting that leukemic B cells from HCL patients are sensitive to venetoclax, but this sensitivity can be overcome by signals from the microenvironment. We propose that the combination of venetoclax with drugs that target the microenvironment might improve its efficacy in HCL.
publishDate 2021
dc.date.none.fl_str_mv 2021-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/212135
Vereertbrugghen, Alexia; Colado, Ana; Gargiulo, Ernesto; Bezares, Raimundo Fernando; Fernández Grecco, Horacio; et al.; In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia; Frontiers Media; Frontiers in Oncology; 11; 598319; 7-2021; 1-7
2234-943X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/212135
identifier_str_mv Vereertbrugghen, Alexia; Colado, Ana; Gargiulo, Ernesto; Bezares, Raimundo Fernando; Fernández Grecco, Horacio; et al.; In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia; Frontiers Media; Frontiers in Oncology; 11; 598319; 7-2021; 1-7
2234-943X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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