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RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells

RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a...

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Autores principales: di Martino, Orsola, Ferris, Margaret A., Hadwiger, Gayla, Sarkar, Soyi, Vu, Anh, Menéndez-Gutiérrez, María P., Ricote, Mercedes, Welch, John S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804561/
https://www.ncbi.nlm.nih.gov/pubmed/34134472
http://dx.doi.org/10.3324/haematol.2021.278603
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author di Martino, Orsola
Ferris, Margaret A.
Hadwiger, Gayla
Sarkar, Soyi
Vu, Anh
Menéndez-Gutiérrez, María P.
Ricote, Mercedes
Welch, John S.
author_facet di Martino, Orsola
Ferris, Margaret A.
Hadwiger, Gayla
Sarkar, Soyi
Vu, Anh
Menéndez-Gutiérrez, María P.
Ricote, Mercedes
Welch, John S.
author_sort di Martino, Orsola
collection PubMed
description RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of constitutive activity that leads to leukemic maturation. Phenotypes of RXRA DT448/9PP appear to differ from those of two other RXRA mutations with forms of constitutive activity (F318A and S427F), in that DT448/9PP activity was resistant to mutations at critical ligand-interacting amino acids (R316A/L326A) and was resistant to pharmacological antagonists, suggesting it may be ligand-independent. These data provide further evidence that activated retinoid X receptors can regulate myeloid maturation and provide a novel constitutively active variant that may be germane for broader studies of retinoid X receptors in other settings.
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spelling pubmed-88045612022-02-23 RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells di Martino, Orsola Ferris, Margaret A. Hadwiger, Gayla Sarkar, Soyi Vu, Anh Menéndez-Gutiérrez, María P. Ricote, Mercedes Welch, John S. Haematologica Article RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of constitutive activity that leads to leukemic maturation. Phenotypes of RXRA DT448/9PP appear to differ from those of two other RXRA mutations with forms of constitutive activity (F318A and S427F), in that DT448/9PP activity was resistant to mutations at critical ligand-interacting amino acids (R316A/L326A) and was resistant to pharmacological antagonists, suggesting it may be ligand-independent. These data provide further evidence that activated retinoid X receptors can regulate myeloid maturation and provide a novel constitutively active variant that may be germane for broader studies of retinoid X receptors in other settings. Fondazione Ferrata Storti 2021-06-17 /pmc/articles/PMC8804561/ /pubmed/34134472 http://dx.doi.org/10.3324/haematol.2021.278603 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
di Martino, Orsola
Ferris, Margaret A.
Hadwiger, Gayla
Sarkar, Soyi
Vu, Anh
Menéndez-Gutiérrez, María P.
Ricote, Mercedes
Welch, John S.
RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells
title RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells
title_full RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells
title_fullStr RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells
title_full_unstemmed RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells
title_short RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells
title_sort rxra dt448/9pp generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804561/
https://www.ncbi.nlm.nih.gov/pubmed/34134472
http://dx.doi.org/10.3324/haematol.2021.278603
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