{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:05:37Z","timestamp":1791385537020,"version":"4.3.3"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> The ligand-activated transcription factors, nuclear hormone receptors (NHRs), remain unexplored in hematological malignancies except for retinoic acid receptor alpha (<jats:italic>RARA<\/jats:italic>).<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Here we profiled the expression of various NHRs and their coregulators in Chronic myeloid leukemia (CML) cell lines and identified a significant differential expression pattern between inherently imatinib mesylate (IM)-sensitive and resistant cell lines.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Retinoid-X-receptor alpha (<jats:italic>RXRA<\/jats:italic>) was downregulated in CML cell lines inherently resistant to IM and in primary CML CD34<jats:sup>+<\/jats:sup> cells. Pre-treatment with clinically relevant RXRA ligands improved sensitivity to IM <jats:italic>in-vitro<\/jats:italic> in both CML cell lines and primary CML cells. This combination effectively reduced the viability and colony-forming capacity of CML CD34<jats:sup>+<\/jats:sup> cells <jats:italic>in-vitro. In-vivo,<\/jats:italic> this combination reduced leukemic burden and prolonged survival. Overexpression (OE) of <jats:italic>RXRA<\/jats:italic> inhibited proliferation and improved sensitivity to IM <jats:italic>in-vitro<\/jats:italic>. <jats:italic>In-vivo, RXRA<\/jats:italic> OE cells showed reduced engraftment of cells in the bone marrow, improved sensitivity to IM, and prolonged survival. Both <jats:italic>RXRA OE<\/jats:italic> and ligand treatment markedly reduced BCR::ABL1 downstream kinase activation, activating apoptotic cascades and improving sensitivity to IM. Importantly, RXRA OE also led to the disruption of the oxidative capacity of these cells.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Combining IM with clinically available RXRA ligands could form an alternative treatment strategy in CML patients with suboptimal response to IM.<\/jats:p>","DOI":"10.3389\/fphar.2023.1187066","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T05:24:13Z","timestamp":1685510653000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Modulating retinoid-X-receptor alpha (RXRA) expression sensitizes chronic myeloid leukemia cells to imatinib in vitro and reduces disease burden in vivo"],"prefix":"10.3389","volume":"14","author":[{"given":"Bharathi M.","family":"Rajamani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raveen Stephen Stallon","family":"Illangeswaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther Sathya Bama","family":"Benjamin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balaji","family":"Balakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Zechariah Paul","family":"Jebanesan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saswati","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aswin Anand","family":"Pai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakhi Thalayattu","family":"Vidhyadharan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajith","family":"Mohan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreeja","family":"Karathedath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aby","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Mathews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaji R.","family":"Velayudhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poonkuzhali","family":"Balasubramanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1182\/blood-2016-05-714089","article-title":"Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI","volume":"129","author":"Agarwal","year":"2017","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"8754","DOI":"10.1158\/0008-5472.CAN-04-3569","article-title":"Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor","volume":"65","author":"Altucci","year":"2005","journal-title":"Cancer Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1194\/jlr.D019745","article-title":"A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS\/MS","volume":"53","author":"Arnold","year":"2012","journal-title":"J. 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