Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation

Autores
Palacios, F.; Abreu, C.; Prieto, D.; Morande, Pablo Elías; Ruiz, S.; Fernández Calero, T.; Naya, H.; Libisch, G.; Robello, C.; Landoni, A. I.; Gabus, R.; Dighiero, G.; Oppezzo, Pablo
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal B cells arrested in G0/G1 stages that coexist, in different proportions, with proliferative B cells. Understanding the crosstalk between the proliferative subsets and their milieu could provide clues on CLL biology. We previously identified one of these subpopulations in the peripheral blood from unmutated patients that appears to be a hallmark of a progressive disease. Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis comparing the global mRNA and microRNA expression of this leukemic subpopulation, and compared it with their quiescent counterparts. Our results suggest that proliferation of this fraction depend on microRNA-22 overexpression that induces phosphatase and tensin homolog downregulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B cells switches on PI3K/AKT, leading to downregulation of p27-Kip1 and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40 ligand/interleukin-4 and, more importantly, that this regulatory loop is also present in lymph nodes from progressive unmutated patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide additional rationale for the usage of PI3K inhibitors.
Fil: Palacios, F.. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay
Fil: Abreu, C.. Instituto Pasteur de Montevideo; Uruguay
Fil: Prieto, D.. Instituto Pasteur de Montevideo; Uruguay
Fil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Pasteur de Montevideo; Uruguay
Fil: Ruiz, S.. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Fil: Fernández Calero, T.. Instituto Pasteur de Montevideo; Uruguay
Fil: Naya, H.. Instituto Pasteur de Montevideo; Uruguay
Fil: Libisch, G.. Instituto Pasteur de Montevideo; Uruguay
Fil: Robello, C.. Instituto Pasteur de Montevideo; Uruguay
Fil: Landoni, A. I.. Hospital Maciel Montevideo; Uruguay
Fil: Gabus, R.. Hospital Maciel; Uruguay
Fil: Dighiero, G.. Hospital Maciel; Uruguay
Fil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay
Materia
PI3K/AKT pathway
Chronic lymphocytic leukemia
microRNA-22
cell proliferation
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/85311
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/85311
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferationPalacios, F.Abreu, C.Prieto, D.Morande, Pablo ElíasRuiz, S.Fernández Calero, T.Naya, H.Libisch, G.Robello, C.Landoni, A. I.Gabus, R.Dighiero, G.Oppezzo, PabloPI3K/AKT pathwayChronic lymphocytic leukemiamicroRNA-22cell proliferationhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal B cells arrested in G0/G1 stages that coexist, in different proportions, with proliferative B cells. Understanding the crosstalk between the proliferative subsets and their milieu could provide clues on CLL biology. We previously identified one of these subpopulations in the peripheral blood from unmutated patients that appears to be a hallmark of a progressive disease. Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis comparing the global mRNA and microRNA expression of this leukemic subpopulation, and compared it with their quiescent counterparts. Our results suggest that proliferation of this fraction depend on microRNA-22 overexpression that induces phosphatase and tensin homolog downregulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B cells switches on PI3K/AKT, leading to downregulation of p27-Kip1 and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40 ligand/interleukin-4 and, more importantly, that this regulatory loop is also present in lymph nodes from progressive unmutated patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide additional rationale for the usage of PI3K inhibitors.Fil: Palacios, F.. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; UruguayFil: Abreu, C.. Instituto Pasteur de Montevideo; UruguayFil: Prieto, D.. Instituto Pasteur de Montevideo; UruguayFil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Pasteur de Montevideo; UruguayFil: Ruiz, S.. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayFil: Fernández Calero, T.. Instituto Pasteur de Montevideo; UruguayFil: Naya, H.. Instituto Pasteur de Montevideo; UruguayFil: Libisch, G.. Instituto Pasteur de Montevideo; UruguayFil: Robello, C.. Instituto Pasteur de Montevideo; UruguayFil: Landoni, A. I.. Hospital Maciel Montevideo; UruguayFil: Gabus, R.. Hospital Maciel; UruguayFil: Dighiero, G.. Hospital Maciel; UruguayFil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; UruguayNature Publishing Group2015-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85311Palacios, F.; Abreu, C.; Prieto, D.; Morande, Pablo Elías; Ruiz, S.; et al.; Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation; Nature Publishing Group; Leukemia; 29; 1; 1-2015; 115-1250887-6924CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/leu.2014.158info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/leu2014158info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:56:33Zoai:ri.conicet.gov.ar:11336/85311instacron: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:34982025-09-29 09:56:34.085CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation
title Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation
spellingShingle Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation
Palacios, F.
PI3K/AKT pathway
Chronic lymphocytic leukemia
microRNA-22
cell proliferation
title_short Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation
title_full Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation
title_fullStr Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation
title_full_unstemmed Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation
title_sort Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation
dc.creator.none.fl_str_mv Palacios, F.
Abreu, C.
Prieto, D.
Morande, Pablo Elías
Ruiz, S.
Fernández Calero, T.
Naya, H.
Libisch, G.
Robello, C.
Landoni, A. I.
Gabus, R.
Dighiero, G.
Oppezzo, Pablo
author Palacios, F.
author_facet Palacios, F.
Abreu, C.
Prieto, D.
Morande, Pablo Elías
Ruiz, S.
Fernández Calero, T.
Naya, H.
Libisch, G.
Robello, C.
Landoni, A. I.
Gabus, R.
Dighiero, G.
Oppezzo, Pablo
author_role author
author2 Abreu, C.
Prieto, D.
Morande, Pablo Elías
Ruiz, S.
Fernández Calero, T.
Naya, H.
Libisch, G.
Robello, C.
Landoni, A. I.
Gabus, R.
Dighiero, G.
Oppezzo, Pablo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PI3K/AKT pathway
Chronic lymphocytic leukemia
microRNA-22
cell proliferation
topic PI3K/AKT pathway
Chronic lymphocytic leukemia
microRNA-22
cell proliferation
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal B cells arrested in G0/G1 stages that coexist, in different proportions, with proliferative B cells. Understanding the crosstalk between the proliferative subsets and their milieu could provide clues on CLL biology. We previously identified one of these subpopulations in the peripheral blood from unmutated patients that appears to be a hallmark of a progressive disease. Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis comparing the global mRNA and microRNA expression of this leukemic subpopulation, and compared it with their quiescent counterparts. Our results suggest that proliferation of this fraction depend on microRNA-22 overexpression that induces phosphatase and tensin homolog downregulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B cells switches on PI3K/AKT, leading to downregulation of p27-Kip1 and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40 ligand/interleukin-4 and, more importantly, that this regulatory loop is also present in lymph nodes from progressive unmutated patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide additional rationale for the usage of PI3K inhibitors.
Fil: Palacios, F.. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay
Fil: Abreu, C.. Instituto Pasteur de Montevideo; Uruguay
Fil: Prieto, D.. Instituto Pasteur de Montevideo; Uruguay
Fil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Pasteur de Montevideo; Uruguay
Fil: Ruiz, S.. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay
Fil: Fernández Calero, T.. Instituto Pasteur de Montevideo; Uruguay
Fil: Naya, H.. Instituto Pasteur de Montevideo; Uruguay
Fil: Libisch, G.. Instituto Pasteur de Montevideo; Uruguay
Fil: Robello, C.. Instituto Pasteur de Montevideo; Uruguay
Fil: Landoni, A. I.. Hospital Maciel Montevideo; Uruguay
Fil: Gabus, R.. Hospital Maciel; Uruguay
Fil: Dighiero, G.. Hospital Maciel; Uruguay
Fil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay
description Chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal B cells arrested in G0/G1 stages that coexist, in different proportions, with proliferative B cells. Understanding the crosstalk between the proliferative subsets and their milieu could provide clues on CLL biology. We previously identified one of these subpopulations in the peripheral blood from unmutated patients that appears to be a hallmark of a progressive disease. Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis comparing the global mRNA and microRNA expression of this leukemic subpopulation, and compared it with their quiescent counterparts. Our results suggest that proliferation of this fraction depend on microRNA-22 overexpression that induces phosphatase and tensin homolog downregulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B cells switches on PI3K/AKT, leading to downregulation of p27-Kip1 and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40 ligand/interleukin-4 and, more importantly, that this regulatory loop is also present in lymph nodes from progressive unmutated patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide additional rationale for the usage of PI3K inhibitors.
publishDate 2015
dc.date.none.fl_str_mv 2015-01
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/11336/85311
Palacios, F.; Abreu, C.; Prieto, D.; Morande, Pablo Elías; Ruiz, S.; et al.; Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation; Nature Publishing Group; Leukemia; 29; 1; 1-2015; 115-125
0887-6924
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85311
identifier_str_mv Palacios, F.; Abreu, C.; Prieto, D.; Morande, Pablo Elías; Ruiz, S.; et al.; Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation; Nature Publishing Group; Leukemia; 29; 1; 1-2015; 115-125
0887-6924
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/leu.2014.158
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/leu2014158
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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