2024-03-28T14:17:15Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/137082023-10-09T08:00:34Zcom_20.500.12105_2145com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2146
Repisalud
author
Di Martino, Orsola
author
Ferris, Margaret A
author
Hadwiger, Gayla
author
Sarkar, Soyi
author
Vu, Anh
author
Menendez-Gutierrez, Maria Piedad
author
Ricote, Mercedes
author
Welch, John S
funder
Ministerio de Ciencia e Innovación (España)
2022-03-02T10:58:54Z
2022-03-02T10:58:54Z
2022-02-01
Di Martino O, Ferris MA, Hadwiger G, Sarkar S, Vu A, Menéndez-Gutiérrez MP, Ricote M, Welch JS. RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells. Haematologica. 2022 Feb 1;107(2):417-426. doi: 10.3324/haematol.2021.278603
0390-6078
http://hdl.handle.net/20.500.12105/13708
34134472
10.3324/haematol.2021.278603
1592-8721
Haematologica
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.
eng
RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells.
journal article
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