Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with pre...

Autores
Glembotsky, Ana Claudia; Sliwa, Dominika; Bluteau, Dominique; Balayn, Nathalie; Marin Oyarzún, Cecilia Paola; Raimbault, Anna; Bordas, Marie; Droin, Nathalie; Pirozhkova, Iryna; Washington, Valance; Goette, Nora Paula; Marta, Rosana Fernanda; Favier, Rémi; Raslova, Hana; Heller, Paula Graciela
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Germline RUNX1 mutations lead to thrombocytopenia and platelet dysfunction in familialplatelet disorder with predisposition to acute myelogenous leukemia. Multiple aspects ofplatelet function are impaired in these patients, associated with altered expression of genesregulated by RUNX1. We aimed to identify RUNX1-targets involved in platelet functionby combining transcriptome analysis of patient and shRUNX1-transduced megakaryocytes.Downregulated genes included TREM-like transcript (TLT)-1 (TREML1) and the integrinsubunit α2 (ITGA2) of collagen receptor α2β1, which are involved in platelet aggregationand adhesion, respectively. RUNX1 binding to regions enriched for H3K27Ac marks wasdemonstrated for both genes using chromatin immunoprecipitation. Cloning of theseregions upstream of the respective promoters in lentivirus allowing mCherry reporterexpression showed that RUNX1 positively regulates TREML1 and ITGA2 and thisregulation was abrogated after deletion of RUNX1 sites. TLT-1 content was reduced inpatient megakaryocytes and platelets. A blocking anti-TLT-1 antibody was able to blockaggregation of normal but not patient platelets, whereas recombinant soluble TLT-1potentiated fibrinogen binding to patient platelets, pointing to a role for TLT-1 deficiencyin the platelet function defect. Low levels of α2 integrin subunit were demonstrated inpatient platelets and megakaryocytes, coupled with reduced platelet and megakaryocyteadhesion to collagen, both under static and flow conditions. In conclusion, we show thatgene expression profiling of RUNX1 knock-down or mutated megakaryocytes provides asuitable approach to identify novel RUNX1-targets, among which downregulation ofTREML1 and ITGA2 clearly contribute to the platelet phenotype of familial plateletdisorder with predisposition to acute myelogenous leukemia.
Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Sliwa, Dominika. Institut Gustave Roussy; Francia
Fil: Bluteau, Dominique. Ecole Pratique des Hautes Etudes; Francia. Institut Gustave Roussy; Francia
Fil: Balayn, Nathalie. Institut Gustave Roussy; Francia
Fil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Raimbault, Anna. Institut Gustave Roussy; Francia
Fil: Bordas, Marie. Institut Gustave Roussy; Francia
Fil: Droin, Nathalie. Institut Gustave Roussy; Francia
Fil: Pirozhkova, Iryna. Institut Gustave Roussy; Francia
Fil: Washington, Valance. Universidad de Puerto Rico; Puerto Rico
Fil: Goette, Nora Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Favier, Rémi. Institut Gustave Roussy; Francia
Fil: Raslova, Hana. Institut Gustave Roussy; Francia
Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Materia
PLATELETS
TLT-1
INHERITED THROMBOCYTOPENIAS
COLLAGEN RECEPTOR
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/105268
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemiaGlembotsky, Ana ClaudiaSliwa, DominikaBluteau, DominiqueBalayn, NathalieMarin Oyarzún, Cecilia PaolaRaimbault, AnnaBordas, MarieDroin, NathaliePirozhkova, IrynaWashington, ValanceGoette, Nora PaulaMarta, Rosana FernandaFavier, RémiRaslova, HanaHeller, Paula GracielaPLATELETSTLT-1INHERITED THROMBOCYTOPENIASCOLLAGEN RECEPTORhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Germline RUNX1 mutations lead to thrombocytopenia and platelet dysfunction in familialplatelet disorder with predisposition to acute myelogenous leukemia. Multiple aspects ofplatelet function are impaired in these patients, associated with altered expression of genesregulated by RUNX1. We aimed to identify RUNX1-targets involved in platelet functionby combining transcriptome analysis of patient and shRUNX1-transduced megakaryocytes.Downregulated genes included TREM-like transcript (TLT)-1 (TREML1) and the integrinsubunit α2 (ITGA2) of collagen receptor α2β1, which are involved in platelet aggregationand adhesion, respectively. RUNX1 binding to regions enriched for H3K27Ac marks wasdemonstrated for both genes using chromatin immunoprecipitation. Cloning of theseregions upstream of the respective promoters in lentivirus allowing mCherry reporterexpression showed that RUNX1 positively regulates TREML1 and ITGA2 and thisregulation was abrogated after deletion of RUNX1 sites. TLT-1 content was reduced inpatient megakaryocytes and platelets. A blocking anti-TLT-1 antibody was able to blockaggregation of normal but not patient platelets, whereas recombinant soluble TLT-1potentiated fibrinogen binding to patient platelets, pointing to a role for TLT-1 deficiencyin the platelet function defect. Low levels of α2 integrin subunit were demonstrated inpatient platelets and megakaryocytes, coupled with reduced platelet and megakaryocyteadhesion to collagen, both under static and flow conditions. In conclusion, we show thatgene expression profiling of RUNX1 knock-down or mutated megakaryocytes provides asuitable approach to identify novel RUNX1-targets, among which downregulation ofTREML1 and ITGA2 clearly contribute to the platelet phenotype of familial plateletdisorder with predisposition to acute myelogenous leukemia.Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Sliwa, Dominika. Institut Gustave Roussy; FranciaFil: Bluteau, Dominique. Ecole Pratique des Hautes Etudes; Francia. Institut Gustave Roussy; FranciaFil: Balayn, Nathalie. Institut Gustave Roussy; FranciaFil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Raimbault, Anna. Institut Gustave Roussy; FranciaFil: Bordas, Marie. Institut Gustave Roussy; FranciaFil: Droin, Nathalie. Institut Gustave Roussy; FranciaFil: Pirozhkova, Iryna. Institut Gustave Roussy; FranciaFil: Washington, Valance. Universidad de Puerto Rico; Puerto RicoFil: Goette, Nora Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Favier, Rémi. Institut Gustave Roussy; FranciaFil: Raslova, Hana. Institut Gustave Roussy; FranciaFil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFerrata Storti Foundation2018-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/105268Glembotsky, Ana Claudia; Sliwa, Dominika; Bluteau, Dominique; Balayn, Nathalie; Marin Oyarzún, Cecilia Paola; et al.; Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia; Ferrata Storti Foundation; Haematologica; 104; 6; 12-2018; 1244-12551592-8721CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.haematologica.org/lookup/doi/10.3324/haematol.2018.188904info:eu-repo/semantics/altIdentifier/doi/10.3324/haematol.2018.188904info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:47Zoai:ri.conicet.gov.ar:11336/105268instacron: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:34982025-09-03 09:59:47.426CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia
title Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia
spellingShingle Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia
Glembotsky, Ana Claudia
PLATELETS
TLT-1
INHERITED THROMBOCYTOPENIAS
COLLAGEN RECEPTOR
title_short Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia
title_full Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia
title_fullStr Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia
title_full_unstemmed Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia
title_sort Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia
dc.creator.none.fl_str_mv Glembotsky, Ana Claudia
Sliwa, Dominika
Bluteau, Dominique
Balayn, Nathalie
Marin Oyarzún, Cecilia Paola
Raimbault, Anna
Bordas, Marie
Droin, Nathalie
Pirozhkova, Iryna
Washington, Valance
Goette, Nora Paula
Marta, Rosana Fernanda
Favier, Rémi
Raslova, Hana
Heller, Paula Graciela
author Glembotsky, Ana Claudia
author_facet Glembotsky, Ana Claudia
Sliwa, Dominika
Bluteau, Dominique
Balayn, Nathalie
Marin Oyarzún, Cecilia Paola
Raimbault, Anna
Bordas, Marie
Droin, Nathalie
Pirozhkova, Iryna
Washington, Valance
Goette, Nora Paula
Marta, Rosana Fernanda
Favier, Rémi
Raslova, Hana
Heller, Paula Graciela
author_role author
author2 Sliwa, Dominika
Bluteau, Dominique
Balayn, Nathalie
Marin Oyarzún, Cecilia Paola
Raimbault, Anna
Bordas, Marie
Droin, Nathalie
Pirozhkova, Iryna
Washington, Valance
Goette, Nora Paula
Marta, Rosana Fernanda
Favier, Rémi
Raslova, Hana
Heller, Paula Graciela
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PLATELETS
TLT-1
INHERITED THROMBOCYTOPENIAS
COLLAGEN RECEPTOR
topic PLATELETS
TLT-1
INHERITED THROMBOCYTOPENIAS
COLLAGEN RECEPTOR
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Germline RUNX1 mutations lead to thrombocytopenia and platelet dysfunction in familialplatelet disorder with predisposition to acute myelogenous leukemia. Multiple aspects ofplatelet function are impaired in these patients, associated with altered expression of genesregulated by RUNX1. We aimed to identify RUNX1-targets involved in platelet functionby combining transcriptome analysis of patient and shRUNX1-transduced megakaryocytes.Downregulated genes included TREM-like transcript (TLT)-1 (TREML1) and the integrinsubunit α2 (ITGA2) of collagen receptor α2β1, which are involved in platelet aggregationand adhesion, respectively. RUNX1 binding to regions enriched for H3K27Ac marks wasdemonstrated for both genes using chromatin immunoprecipitation. Cloning of theseregions upstream of the respective promoters in lentivirus allowing mCherry reporterexpression showed that RUNX1 positively regulates TREML1 and ITGA2 and thisregulation was abrogated after deletion of RUNX1 sites. TLT-1 content was reduced inpatient megakaryocytes and platelets. A blocking anti-TLT-1 antibody was able to blockaggregation of normal but not patient platelets, whereas recombinant soluble TLT-1potentiated fibrinogen binding to patient platelets, pointing to a role for TLT-1 deficiencyin the platelet function defect. Low levels of α2 integrin subunit were demonstrated inpatient platelets and megakaryocytes, coupled with reduced platelet and megakaryocyteadhesion to collagen, both under static and flow conditions. In conclusion, we show thatgene expression profiling of RUNX1 knock-down or mutated megakaryocytes provides asuitable approach to identify novel RUNX1-targets, among which downregulation ofTREML1 and ITGA2 clearly contribute to the platelet phenotype of familial plateletdisorder with predisposition to acute myelogenous leukemia.
Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Sliwa, Dominika. Institut Gustave Roussy; Francia
Fil: Bluteau, Dominique. Ecole Pratique des Hautes Etudes; Francia. Institut Gustave Roussy; Francia
Fil: Balayn, Nathalie. Institut Gustave Roussy; Francia
Fil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Raimbault, Anna. Institut Gustave Roussy; Francia
Fil: Bordas, Marie. Institut Gustave Roussy; Francia
Fil: Droin, Nathalie. Institut Gustave Roussy; Francia
Fil: Pirozhkova, Iryna. Institut Gustave Roussy; Francia
Fil: Washington, Valance. Universidad de Puerto Rico; Puerto Rico
Fil: Goette, Nora Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Favier, Rémi. Institut Gustave Roussy; Francia
Fil: Raslova, Hana. Institut Gustave Roussy; Francia
Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
description Germline RUNX1 mutations lead to thrombocytopenia and platelet dysfunction in familialplatelet disorder with predisposition to acute myelogenous leukemia. Multiple aspects ofplatelet function are impaired in these patients, associated with altered expression of genesregulated by RUNX1. We aimed to identify RUNX1-targets involved in platelet functionby combining transcriptome analysis of patient and shRUNX1-transduced megakaryocytes.Downregulated genes included TREM-like transcript (TLT)-1 (TREML1) and the integrinsubunit α2 (ITGA2) of collagen receptor α2β1, which are involved in platelet aggregationand adhesion, respectively. RUNX1 binding to regions enriched for H3K27Ac marks wasdemonstrated for both genes using chromatin immunoprecipitation. Cloning of theseregions upstream of the respective promoters in lentivirus allowing mCherry reporterexpression showed that RUNX1 positively regulates TREML1 and ITGA2 and thisregulation was abrogated after deletion of RUNX1 sites. TLT-1 content was reduced inpatient megakaryocytes and platelets. A blocking anti-TLT-1 antibody was able to blockaggregation of normal but not patient platelets, whereas recombinant soluble TLT-1potentiated fibrinogen binding to patient platelets, pointing to a role for TLT-1 deficiencyin the platelet function defect. Low levels of α2 integrin subunit were demonstrated inpatient platelets and megakaryocytes, coupled with reduced platelet and megakaryocyteadhesion to collagen, both under static and flow conditions. In conclusion, we show thatgene expression profiling of RUNX1 knock-down or mutated megakaryocytes provides asuitable approach to identify novel RUNX1-targets, among which downregulation ofTREML1 and ITGA2 clearly contribute to the platelet phenotype of familial plateletdisorder with predisposition to acute myelogenous leukemia.
publishDate 2018
dc.date.none.fl_str_mv 2018-12
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/11336/105268
Glembotsky, Ana Claudia; Sliwa, Dominika; Bluteau, Dominique; Balayn, Nathalie; Marin Oyarzún, Cecilia Paola; et al.; Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia; Ferrata Storti Foundation; Haematologica; 104; 6; 12-2018; 1244-1255
1592-8721
CONICET Digital
CONICET
url http://hdl.handle.net/11336/105268
identifier_str_mv Glembotsky, Ana Claudia; Sliwa, Dominika; Bluteau, Dominique; Balayn, Nathalie; Marin Oyarzún, Cecilia Paola; et al.; Downregulation of TREM-like transcript (TLT)-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia; Ferrata Storti Foundation; Haematologica; 104; 6; 12-2018; 1244-1255
1592-8721
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.haematologica.org/lookup/doi/10.3324/haematol.2018.188904
info:eu-repo/semantics/altIdentifier/doi/10.3324/haematol.2018.188904
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Ferrata Storti Foundation
publisher.none.fl_str_mv Ferrata Storti Foundation
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 13.13397

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