{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T02:19:44Z","timestamp":1770430784906,"version":"3.49.0"},"reference-count":48,"publisher":"Rockefeller University Press","issue":"8","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,4,19]]},"abstract":"<jats:p>PML\u2013RARA was proposed to initiate acute promyelocytic leukemia (APL) through PML\u2013RARA homodimer\u2013triggered repression. Here, we examined the nature of the PML\u2013RARA protein complex and of its DNA targets in APL cells. Using a selection\/amplification approach, we demonstrate that PML\u2013RARA targets consist of two AGGTCA elements in an astonishing variety of orientations and spacings, pointing to highly relaxed structural constrains for DNA binding and identifying a major gain of function of this oncogene. PML\u2013RARA-specific response elements were identified, which all conveyed a major transcriptional response to RA only in APL cells. In these cells, we demonstrate that PML\u2013RARA oligomers are complexed to RXR. Directly probing PML\u2013RARA function in APL cells, we found that the differentiation enhancer cyclic AMP (cAMP) boosted transcriptional activation by RA. cAMP also reversed the normal silencing (subordination) of the transactivating function of RXR when bound to RARA or PML\u2013RARA, demonstrating that the alternate rexinoid\/cAMP-triggered APL differentiation pathway also activates PML\u2013RARA targets. Finally, cAMP restored both RA-triggered differentiation and PML\u2013RARA transcriptional activation in mutant RA-resistant APL cells. Collectively, our findings directly demonstrate that APL cell differentiation parallels transcriptional activation through PML\u2013RARA-RXR oligomers and that those are functionally targeted by cAMP, identifying this agent as another oncogene-targeted therapy.<\/jats:p>","DOI":"10.1084\/jem.20032226","type":"journal-article","created":{"date-parts":[[2004,4,19]],"date-time":"2004-04-19T18:37:59Z","timestamp":1082399879000},"page":"1163-1174","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":132,"title":["PML\u2013RARA-RXR Oligomers Mediate Retinoid and Rexinoid\/cAMP Cross-Talk in Acute Promyelocytic Leukemia Cell Differentiation"],"prefix":"10.1084","volume":"199","author":[{"given":"Dmitrii","family":"Kamashev","sequence":"first","affiliation":[{"name":"CNRS UPR9051, Ho\u0302pital St. Louis, Laboratoire associe\u0301 N\u00b0 11, Comite\u0301 de Paris de la Ligue contre le Cancer, Universite\u0301 de Paris VII, 75475 Paris, Cedex 10, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Vitoux","sequence":"additional","affiliation":[{"name":"CNRS UPR9051, Ho\u0302pital St. Louis, Laboratoire associe\u0301 N\u00b0 11, Comite\u0301 de Paris de la Ligue contre le Cancer, Universite\u0301 de Paris VII, 75475 Paris, Cedex 10, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugues","family":"de The\u0301","sequence":"additional","affiliation":[{"name":"CNRS UPR9051, Ho\u0302pital St. Louis, Laboratoire associe\u0301 N\u00b0 11, Comite\u0301 de Paris de la Ligue contre le Cancer, Universite\u0301 de Paris VII, 75475 Paris, Cedex 10, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2004,4,19]]},"reference":[{"key":"2023072512245313400_BIB1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0303-7207(96)03794-X","volume":"119","year":"1996","journal-title":"Mol. 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