Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus

Autores
Hu, Zhenbo; Negrotto, Soledad; Gu, Xiaorong; Mahfouz, Reda; Ng, Kwok Peng; Ebrahem, Quteba; Copelan, Edward; Singh, Harinder; Maciejewski, Jaroslaw P.; Saunthararajah, Yogen
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The cytosine analogue decitabine alters hematopoietic differentiation. For example, decitabine treatment increases self-renewal of normal hematopoietic stem cells. The mechanisms underlying decitabine-induced shifts in differentiation are poorly understood, but likely relate to the ability of decitabine to deplete the chromatin-modifying enzyme DNA methyltransferase 1 (DNMT1), which plays a central role in transcription repression. HOXB4 is a transcription factor that promotes hematopoietic stem cell self-renewal. In hematopoietic precursors induced to differentiate by the lineage-specifying transcription factor Pu.1 or by the cytokine granulocyte-colony stimulating factor, there is rapid repression of HOXB4 and other stem cell genes. Depletion of DNMT1 using shRNA or decitabine prevents HOXB4 repression by Pu.1 or granulocyte-colony stimulating factor and maintains hematopoietic precursor self-renewal. In contrast, depletion of DNMT1 by decitabine 6 hours after the differentiation stimulus, that is, after repression of HOXB4 has occurred, augments differentiation. Therefore, DNMT1 is required for the early repression of stem cell genes, which occurs in response to a differentiation stimulus, providing a mechanistic explanation for the observation that decitabine can maintain or increase hematopoietic stem cell self-renewal in the presence of a differentiation stimulus. Using decitabine to deplete DNMT1 after this early repression phase does not impair progressive differentiation. ©2010 AACR.
Fil: Hu, Zhenbo. Cleveland Clinic; Estados Unidos
Fil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cleveland Clinic; Estados Unidos
Fil: Gu, Xiaorong. Cleveland Clinic; Estados Unidos
Fil: Mahfouz, Reda. Cleveland Clinic; Estados Unidos
Fil: Ng, Kwok Peng. Cleveland Clinic; Estados Unidos
Fil: Ebrahem, Quteba. Cleveland Clinic; Estados Unidos
Fil: Copelan, Edward. Cleveland Clinic; Estados Unidos
Fil: Singh, Harinder. University of Chicago; Estados Unidos
Fil: Maciejewski, Jaroslaw P.. Cleveland Clinic; Estados Unidos
Fil: Saunthararajah, Yogen. Cleveland Clinic; Estados Unidos
Materia
Decitabine
Acute Myeloid Leukemia
Hematopoietic stem cells
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:11336/52946
Acceder
id CONICETDig_83501a434bae112ea5593a86e1e12c52
oai_identifier_str oai:ri.conicet.gov.ar:11336/52946
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulusHu, ZhenboNegrotto, SoledadGu, XiaorongMahfouz, RedaNg, Kwok PengEbrahem, QutebaCopelan, EdwardSingh, HarinderMaciejewski, Jaroslaw P.Saunthararajah, YogenDecitabineAcute Myeloid LeukemiaHematopoietic stem cellshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The cytosine analogue decitabine alters hematopoietic differentiation. For example, decitabine treatment increases self-renewal of normal hematopoietic stem cells. The mechanisms underlying decitabine-induced shifts in differentiation are poorly understood, but likely relate to the ability of decitabine to deplete the chromatin-modifying enzyme DNA methyltransferase 1 (DNMT1), which plays a central role in transcription repression. HOXB4 is a transcription factor that promotes hematopoietic stem cell self-renewal. In hematopoietic precursors induced to differentiate by the lineage-specifying transcription factor Pu.1 or by the cytokine granulocyte-colony stimulating factor, there is rapid repression of HOXB4 and other stem cell genes. Depletion of DNMT1 using shRNA or decitabine prevents HOXB4 repression by Pu.1 or granulocyte-colony stimulating factor and maintains hematopoietic precursor self-renewal. In contrast, depletion of DNMT1 by decitabine 6 hours after the differentiation stimulus, that is, after repression of HOXB4 has occurred, augments differentiation. Therefore, DNMT1 is required for the early repression of stem cell genes, which occurs in response to a differentiation stimulus, providing a mechanistic explanation for the observation that decitabine can maintain or increase hematopoietic stem cell self-renewal in the presence of a differentiation stimulus. Using decitabine to deplete DNMT1 after this early repression phase does not impair progressive differentiation. ©2010 AACR.Fil: Hu, Zhenbo. Cleveland Clinic; Estados UnidosFil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cleveland Clinic; Estados UnidosFil: Gu, Xiaorong. Cleveland Clinic; Estados UnidosFil: Mahfouz, Reda. Cleveland Clinic; Estados UnidosFil: Ng, Kwok Peng. Cleveland Clinic; Estados UnidosFil: Ebrahem, Quteba. Cleveland Clinic; Estados UnidosFil: Copelan, Edward. Cleveland Clinic; Estados UnidosFil: Singh, Harinder. University of Chicago; Estados UnidosFil: Maciejewski, Jaroslaw P.. Cleveland Clinic; Estados UnidosFil: Saunthararajah, Yogen. Cleveland Clinic; Estados UnidosAmerican Association for Cancer Research2010-06info: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/11336/52946Hu, Zhenbo; Negrotto, Soledad; Gu, Xiaorong; Mahfouz, Reda; Ng, Kwok Peng; et al.; Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus; American Association for Cancer Research; Molecular Cancer Therapeutics; 9; 6; 6-2010; 1536-15431535-7163CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1158/1535-7163.MCT-10-0191info:eu-repo/semantics/altIdentifier/url/http://mct.aacrjournals.org/content/9/6/1536info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:06:14Zoai:ri.conicet.gov.ar:11336/52946instacron: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 10:06:15.105CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
title Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
spellingShingle Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
Hu, Zhenbo
Decitabine
Acute Myeloid Leukemia
Hematopoietic stem cells
title_short Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
title_full Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
title_fullStr Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
title_full_unstemmed Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
title_sort Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
dc.creator.none.fl_str_mv Hu, Zhenbo
Negrotto, Soledad
Gu, Xiaorong
Mahfouz, Reda
Ng, Kwok Peng
Ebrahem, Quteba
Copelan, Edward
Singh, Harinder
Maciejewski, Jaroslaw P.
Saunthararajah, Yogen
author Hu, Zhenbo
author_facet Hu, Zhenbo
Negrotto, Soledad
Gu, Xiaorong
Mahfouz, Reda
Ng, Kwok Peng
Ebrahem, Quteba
Copelan, Edward
Singh, Harinder
Maciejewski, Jaroslaw P.
Saunthararajah, Yogen
author_role author
author2 Negrotto, Soledad
Gu, Xiaorong
Mahfouz, Reda
Ng, Kwok Peng
Ebrahem, Quteba
Copelan, Edward
Singh, Harinder
Maciejewski, Jaroslaw P.
Saunthararajah, Yogen
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Decitabine
Acute Myeloid Leukemia
Hematopoietic stem cells
topic Decitabine
Acute Myeloid Leukemia
Hematopoietic stem cells
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The cytosine analogue decitabine alters hematopoietic differentiation. For example, decitabine treatment increases self-renewal of normal hematopoietic stem cells. The mechanisms underlying decitabine-induced shifts in differentiation are poorly understood, but likely relate to the ability of decitabine to deplete the chromatin-modifying enzyme DNA methyltransferase 1 (DNMT1), which plays a central role in transcription repression. HOXB4 is a transcription factor that promotes hematopoietic stem cell self-renewal. In hematopoietic precursors induced to differentiate by the lineage-specifying transcription factor Pu.1 or by the cytokine granulocyte-colony stimulating factor, there is rapid repression of HOXB4 and other stem cell genes. Depletion of DNMT1 using shRNA or decitabine prevents HOXB4 repression by Pu.1 or granulocyte-colony stimulating factor and maintains hematopoietic precursor self-renewal. In contrast, depletion of DNMT1 by decitabine 6 hours after the differentiation stimulus, that is, after repression of HOXB4 has occurred, augments differentiation. Therefore, DNMT1 is required for the early repression of stem cell genes, which occurs in response to a differentiation stimulus, providing a mechanistic explanation for the observation that decitabine can maintain or increase hematopoietic stem cell self-renewal in the presence of a differentiation stimulus. Using decitabine to deplete DNMT1 after this early repression phase does not impair progressive differentiation. ©2010 AACR.
Fil: Hu, Zhenbo. Cleveland Clinic; Estados Unidos
Fil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cleveland Clinic; Estados Unidos
Fil: Gu, Xiaorong. Cleveland Clinic; Estados Unidos
Fil: Mahfouz, Reda. Cleveland Clinic; Estados Unidos
Fil: Ng, Kwok Peng. Cleveland Clinic; Estados Unidos
Fil: Ebrahem, Quteba. Cleveland Clinic; Estados Unidos
Fil: Copelan, Edward. Cleveland Clinic; Estados Unidos
Fil: Singh, Harinder. University of Chicago; Estados Unidos
Fil: Maciejewski, Jaroslaw P.. Cleveland Clinic; Estados Unidos
Fil: Saunthararajah, Yogen. Cleveland Clinic; Estados Unidos
description The cytosine analogue decitabine alters hematopoietic differentiation. For example, decitabine treatment increases self-renewal of normal hematopoietic stem cells. The mechanisms underlying decitabine-induced shifts in differentiation are poorly understood, but likely relate to the ability of decitabine to deplete the chromatin-modifying enzyme DNA methyltransferase 1 (DNMT1), which plays a central role in transcription repression. HOXB4 is a transcription factor that promotes hematopoietic stem cell self-renewal. In hematopoietic precursors induced to differentiate by the lineage-specifying transcription factor Pu.1 or by the cytokine granulocyte-colony stimulating factor, there is rapid repression of HOXB4 and other stem cell genes. Depletion of DNMT1 using shRNA or decitabine prevents HOXB4 repression by Pu.1 or granulocyte-colony stimulating factor and maintains hematopoietic precursor self-renewal. In contrast, depletion of DNMT1 by decitabine 6 hours after the differentiation stimulus, that is, after repression of HOXB4 has occurred, augments differentiation. Therefore, DNMT1 is required for the early repression of stem cell genes, which occurs in response to a differentiation stimulus, providing a mechanistic explanation for the observation that decitabine can maintain or increase hematopoietic stem cell self-renewal in the presence of a differentiation stimulus. Using decitabine to deplete DNMT1 after this early repression phase does not impair progressive differentiation. ©2010 AACR.
publishDate 2010
dc.date.none.fl_str_mv 2010-06
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/11336/52946
Hu, Zhenbo; Negrotto, Soledad; Gu, Xiaorong; Mahfouz, Reda; Ng, Kwok Peng; et al.; Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus; American Association for Cancer Research; Molecular Cancer Therapeutics; 9; 6; 6-2010; 1536-1543
1535-7163
CONICET Digital
CONICET
url http://hdl.handle.net/11336/52946
identifier_str_mv Hu, Zhenbo; Negrotto, Soledad; Gu, Xiaorong; Mahfouz, Reda; Ng, Kwok Peng; et al.; Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus; American Association for Cancer Research; Molecular Cancer Therapeutics; 9; 6; 6-2010; 1536-1543
1535-7163
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1158/1535-7163.MCT-10-0191
info:eu-repo/semantics/altIdentifier/url/http://mct.aacrjournals.org/content/9/6/1536
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 Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
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
_version_ 1842269948469051392
score 13.13397

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