Endogenous and combination retinoids are active in myelomonocytic leukemias.

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagoni...

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Detalhes bibliográficos
Autores: Di Martino, Orsola, Niu, Haixia, Hadwiger, Gayla, Kuusanmaki, Heikki, Ferris, Margaret A, Vu, Anh, Beales, Jeremy, Wagner, Carl, Menendez-Gutierrez, Maria Piedad, Ricote, Mercedes, Heckman, Caroline, Welch, John S
Tipo de documento: artigo
Data de publicação:2021
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositório:Repisalud
Idioma:inglês
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/13713
Acesso em linha:http://hdl.handle.net/20.500.12105/13713
Access Level:Acceso aberto
Palavra-chave:Leukemia, Promyelocytic, Acute
Retinoids
Animals
Cell Differentiation
Mice
Receptors, Retinoic Acid
Tretinoin
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spelling Endogenous and combination retinoids are active in myelomonocytic leukemias.Di Martino, OrsolaNiu, HaixiaHadwiger, GaylaKuusanmaki, HeikkiFerris, Margaret AVu, AnhBeales, JeremyWagner, CarlMenendez-Gutierrez, Maria PiedadRicote, MercedesHeckman, CarolineWelch, John SLeukemia, Promyelocytic, AcuteRetinoidsAnimalsCell DifferentiationMiceReceptors, Retinoic AcidTretinoinRetinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond acute promyelocytic leukemia.Fondazione Ferrata StortiMinisterio de Ciencia e Innovación (España)Fundación ProCNIC20222022-03-0320212021-04-0120212021-04-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/13713reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/137132026-06-12T12:43:37Z
dc.title.none.fl_str_mv Endogenous and combination retinoids are active in myelomonocytic leukemias.
title Endogenous and combination retinoids are active in myelomonocytic leukemias.
spellingShingle Endogenous and combination retinoids are active in myelomonocytic leukemias.
Di Martino, Orsola
Leukemia, Promyelocytic, Acute
Retinoids
Animals
Cell Differentiation
Mice
Receptors, Retinoic Acid
Tretinoin
title_short Endogenous and combination retinoids are active in myelomonocytic leukemias.
title_full Endogenous and combination retinoids are active in myelomonocytic leukemias.
title_fullStr Endogenous and combination retinoids are active in myelomonocytic leukemias.
title_full_unstemmed Endogenous and combination retinoids are active in myelomonocytic leukemias.
title_sort Endogenous and combination retinoids are active in myelomonocytic leukemias.
dc.creator.none.fl_str_mv Di Martino, Orsola
Niu, Haixia
Hadwiger, Gayla
Kuusanmaki, Heikki
Ferris, Margaret A
Vu, Anh
Beales, Jeremy
Wagner, Carl
Menendez-Gutierrez, Maria Piedad
Ricote, Mercedes
Heckman, Caroline
Welch, John S
author Di Martino, Orsola
author_facet Di Martino, Orsola
Niu, Haixia
Hadwiger, Gayla
Kuusanmaki, Heikki
Ferris, Margaret A
Vu, Anh
Beales, Jeremy
Wagner, Carl
Menendez-Gutierrez, Maria Piedad
Ricote, Mercedes
Heckman, Caroline
Welch, John S
author_role author
author2 Niu, Haixia
Hadwiger, Gayla
Kuusanmaki, Heikki
Ferris, Margaret A
Vu, Anh
Beales, Jeremy
Wagner, Carl
Menendez-Gutierrez, Maria Piedad
Ricote, Mercedes
Heckman, Caroline
Welch, John S
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Fundación ProCNIC
dc.subject.none.fl_str_mv Leukemia, Promyelocytic, Acute
Retinoids
Animals
Cell Differentiation
Mice
Receptors, Retinoic Acid
Tretinoin
topic Leukemia, Promyelocytic, Acute
Retinoids
Animals
Cell Differentiation
Mice
Receptors, Retinoic Acid
Tretinoin
description Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond acute promyelocytic leukemia.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-04-01
2021
2021-04-01
2022
2022-03-03
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/13713
url http://hdl.handle.net/20.500.12105/13713
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial 4.0 Internacional
http://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial 4.0 Internacional
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Fondazione Ferrata Storti
publisher.none.fl_str_mv Fondazione Ferrata Storti
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869409330443321344
score 15.812429

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