Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression

Autores
Bluteau, Dominique; Glembotsky, Ana Claudia; Raimbault, Anna; Balayn, Nathalie; Gilles, Laure; Rameau, Philippe; Nurden, Paquita; Alessi, Marie Christine; Debili, Najet; Vainchenker, William; Heller, Paula Graciela; Favier, Remi; Raslova, Hana
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
FPD/AML is a familial platelet disorder characterized by platelet defects, predisposition to acute myelogenous leukemia (AML) and germ-line heterozygous RUNX1 alterations. Here we studied the in vitro megakaryopoiesis of three FPD/AML pedigrees. A 60-80% decrease in the output of megakaryocytes (MK) from CD34+ was observed. MK ploidy level was low and mature MK displayed a major defect in proplatelet formation. To explain these defects, we focused on myosin II expression as RUNX1 has been shown to regulate MYL9 and MYH10 in an inverse way. In FPD/AML MK, expression of MYL9 and MYH9 was decreased while MYH10 expression was increased and the MYH10 protein was still present in the cytoplasm of mature MK. Myosin II activity inhibition by blebbistatin rescued the ploidy defect of FPD/AML MK. Finally, we demonstrate that MYH9 is a direct target of RUNX1 by chromatin immunoprecipitation and luciferase assays and we identified new RUNX1 binding sites in the MYL9 promoter region. Together, these results demonstrate that the defects in megakaryopoiesis observed in FPD/AML are, in part, related to a deregulation of myosin IIA and IIB expression leading to both a defect in ploidization and proplatelet formation.
Fil: Bluteau, Dominique. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Glembotsky, Ana Claudia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. 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 National de la Santé et de la Recherche Médicale; Francia
Fil: Balayn, Nathalie. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Gilles, Laure. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Rameau, Philippe. Institut Gustave Roussy; Francia
Fil: Nurden, Paquita. No especifíca;
Fil: Alessi, Marie Christine. Faculte de Medecine La Timone; Francia
Fil: Debili, Najet. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Vainchenker, William. Institut National de la Santé et de la Recherche Médicale; 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
Fil: Favier, Remi. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Raslova, Hana. Institut National de la Santé et de la Recherche Médicale; Francia
Materia
RUNX1
FPD/AML
MYH10
MYL9
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:11336/270769
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/270769
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expressionBluteau, DominiqueGlembotsky, Ana ClaudiaRaimbault, AnnaBalayn, NathalieGilles, LaureRameau, PhilippeNurden, PaquitaAlessi, Marie ChristineDebili, NajetVainchenker, WilliamHeller, Paula GracielaFavier, RemiRaslova, HanaRUNX1FPD/AMLMYH10MYL9https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3FPD/AML is a familial platelet disorder characterized by platelet defects, predisposition to acute myelogenous leukemia (AML) and germ-line heterozygous RUNX1 alterations. Here we studied the in vitro megakaryopoiesis of three FPD/AML pedigrees. A 60-80% decrease in the output of megakaryocytes (MK) from CD34+ was observed. MK ploidy level was low and mature MK displayed a major defect in proplatelet formation. To explain these defects, we focused on myosin II expression as RUNX1 has been shown to regulate MYL9 and MYH10 in an inverse way. In FPD/AML MK, expression of MYL9 and MYH9 was decreased while MYH10 expression was increased and the MYH10 protein was still present in the cytoplasm of mature MK. Myosin II activity inhibition by blebbistatin rescued the ploidy defect of FPD/AML MK. Finally, we demonstrate that MYH9 is a direct target of RUNX1 by chromatin immunoprecipitation and luciferase assays and we identified new RUNX1 binding sites in the MYL9 promoter region. Together, these results demonstrate that the defects in megakaryopoiesis observed in FPD/AML are, in part, related to a deregulation of myosin IIA and IIB expression leading to both a defect in ploidization and proplatelet formation.Fil: Bluteau, Dominique. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Glembotsky, Ana Claudia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. 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 National de la Santé et de la Recherche Médicale; FranciaFil: Balayn, Nathalie. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Gilles, Laure. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Rameau, Philippe. Institut Gustave Roussy; FranciaFil: Nurden, Paquita. No especifíca;Fil: Alessi, Marie Christine. Faculte de Medecine La Timone; FranciaFil: Debili, Najet. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Vainchenker, William. Institut National de la Santé et de la Recherche Médicale; 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; ArgentinaFil: Favier, Remi. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Raslova, Hana. Institut National de la Santé et de la Recherche Médicale; FranciaAmerican Society of Hematology2012-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/270769Bluteau, Dominique; Glembotsky, Ana Claudia; Raimbault, Anna; Balayn, Nathalie; Gilles, Laure; et al.; Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression; American Society of Hematology; Blood; 120; 13; 9-2012; 2708-27180006-4971CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://ashpublications.org/blood/article/120/13/2708/30793/Dysmegakaryopoiesis-of-FPD-AML-pedigrees-withinfo:eu-repo/semantics/altIdentifier/doi/10.1182/blood-2012-04-422337info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:33:31Zoai:ri.conicet.gov.ar:11336/270769instacron: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 09:33:32.162CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression
title Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression
spellingShingle Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression
Bluteau, Dominique
RUNX1
FPD/AML
MYH10
MYL9
title_short Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression
title_full Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression
title_fullStr Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression
title_full_unstemmed Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression
title_sort Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression
dc.creator.none.fl_str_mv Bluteau, Dominique
Glembotsky, Ana Claudia
Raimbault, Anna
Balayn, Nathalie
Gilles, Laure
Rameau, Philippe
Nurden, Paquita
Alessi, Marie Christine
Debili, Najet
Vainchenker, William
Heller, Paula Graciela
Favier, Remi
Raslova, Hana
author Bluteau, Dominique
author_facet Bluteau, Dominique
Glembotsky, Ana Claudia
Raimbault, Anna
Balayn, Nathalie
Gilles, Laure
Rameau, Philippe
Nurden, Paquita
Alessi, Marie Christine
Debili, Najet
Vainchenker, William
Heller, Paula Graciela
Favier, Remi
Raslova, Hana
author_role author
author2 Glembotsky, Ana Claudia
Raimbault, Anna
Balayn, Nathalie
Gilles, Laure
Rameau, Philippe
Nurden, Paquita
Alessi, Marie Christine
Debili, Najet
Vainchenker, William
Heller, Paula Graciela
Favier, Remi
Raslova, Hana
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv RUNX1
FPD/AML
MYH10
MYL9
topic RUNX1
FPD/AML
MYH10
MYL9
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv FPD/AML is a familial platelet disorder characterized by platelet defects, predisposition to acute myelogenous leukemia (AML) and germ-line heterozygous RUNX1 alterations. Here we studied the in vitro megakaryopoiesis of three FPD/AML pedigrees. A 60-80% decrease in the output of megakaryocytes (MK) from CD34+ was observed. MK ploidy level was low and mature MK displayed a major defect in proplatelet formation. To explain these defects, we focused on myosin II expression as RUNX1 has been shown to regulate MYL9 and MYH10 in an inverse way. In FPD/AML MK, expression of MYL9 and MYH9 was decreased while MYH10 expression was increased and the MYH10 protein was still present in the cytoplasm of mature MK. Myosin II activity inhibition by blebbistatin rescued the ploidy defect of FPD/AML MK. Finally, we demonstrate that MYH9 is a direct target of RUNX1 by chromatin immunoprecipitation and luciferase assays and we identified new RUNX1 binding sites in the MYL9 promoter region. Together, these results demonstrate that the defects in megakaryopoiesis observed in FPD/AML are, in part, related to a deregulation of myosin IIA and IIB expression leading to both a defect in ploidization and proplatelet formation.
Fil: Bluteau, Dominique. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Glembotsky, Ana Claudia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. 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 National de la Santé et de la Recherche Médicale; Francia
Fil: Balayn, Nathalie. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Gilles, Laure. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Rameau, Philippe. Institut Gustave Roussy; Francia
Fil: Nurden, Paquita. No especifíca;
Fil: Alessi, Marie Christine. Faculte de Medecine La Timone; Francia
Fil: Debili, Najet. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Vainchenker, William. Institut National de la Santé et de la Recherche Médicale; 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
Fil: Favier, Remi. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Raslova, Hana. Institut National de la Santé et de la Recherche Médicale; Francia
description FPD/AML is a familial platelet disorder characterized by platelet defects, predisposition to acute myelogenous leukemia (AML) and germ-line heterozygous RUNX1 alterations. Here we studied the in vitro megakaryopoiesis of three FPD/AML pedigrees. A 60-80% decrease in the output of megakaryocytes (MK) from CD34+ was observed. MK ploidy level was low and mature MK displayed a major defect in proplatelet formation. To explain these defects, we focused on myosin II expression as RUNX1 has been shown to regulate MYL9 and MYH10 in an inverse way. In FPD/AML MK, expression of MYL9 and MYH9 was decreased while MYH10 expression was increased and the MYH10 protein was still present in the cytoplasm of mature MK. Myosin II activity inhibition by blebbistatin rescued the ploidy defect of FPD/AML MK. Finally, we demonstrate that MYH9 is a direct target of RUNX1 by chromatin immunoprecipitation and luciferase assays and we identified new RUNX1 binding sites in the MYL9 promoter region. Together, these results demonstrate that the defects in megakaryopoiesis observed in FPD/AML are, in part, related to a deregulation of myosin IIA and IIB expression leading to both a defect in ploidization and proplatelet formation.
publishDate 2012
dc.date.none.fl_str_mv 2012-09
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/11336/270769
Bluteau, Dominique; Glembotsky, Ana Claudia; Raimbault, Anna; Balayn, Nathalie; Gilles, Laure; et al.; Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression; American Society of Hematology; Blood; 120; 13; 9-2012; 2708-2718
0006-4971
CONICET Digital
CONICET
url http://hdl.handle.net/11336/270769
identifier_str_mv Bluteau, Dominique; Glembotsky, Ana Claudia; Raimbault, Anna; Balayn, Nathalie; Gilles, Laure; et al.; Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression; American Society of Hematology; Blood; 120; 13; 9-2012; 2708-2718
0006-4971
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://ashpublications.org/blood/article/120/13/2708/30793/Dysmegakaryopoiesis-of-FPD-AML-pedigrees-with
info:eu-repo/semantics/altIdentifier/doi/10.1182/blood-2012-04-422337
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
application/pdf
dc.publisher.none.fl_str_mv American Society of Hematology
publisher.none.fl_str_mv American Society of Hematology
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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