{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:17:59Z","timestamp":1790882279266,"version":"4.1.0"},"reference-count":132,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,8]],"date-time":"2023-07-08T00:00:00Z","timestamp":1688774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO). ATRA\u2019s success has deepened our understanding of the role of the RAR\u03b1 pathway in normal hematopoiesis and leukemogenesis, and it has influenced a generation of cancer drug development. Retinoids have also demonstrated some efficacy in a handful of other disease entities, including as a maintenance therapy for neuroblastoma and in the treatment of cutaneous T-cell lymphomas; nevertheless, the promise of retinoids as a differentiating therapy in acute myeloid leukemia (AML) more broadly, and as a cancer preventative, have largely gone unfulfilled. Recent research into the mechanisms of ATRA resistance and the biomarkers of RAR\u03b1 pathway dysregulation in AML have reinvigorated efforts to successfully deploy retinoid therapy in a broader subset of myeloid malignancies. Recent studies have demonstrated that the bone marrow environment is highly protected from exogenous ATRA via local homeostasis controlled by stromal cells expressing CYP26, a key enzyme responsible for ATRA inactivation. Synthetic CYP26-resistant retinoids such as tamibarotene bypass this stromal protection and have shown superior anti-leukemic effects. Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RAR\u03b1 through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.<\/jats:p>","DOI":"10.3390\/cancers15143535","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T00:47:35Z","timestamp":1688950055000},"page":"3535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8826-0066","authenticated-orcid":false,"given":"Yuya","family":"Nagai","sequence":"first","affiliation":[{"name":"Department of Hematology, Kobe City Medical Center General Hospital, Kobe 650-0047, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0855-9653","authenticated-orcid":false,"given":"Alexander J.","family":"Ambinder","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.blre.2015.01.002","article-title":"An ATRActive future for differentiation therapy in AML","volume":"29","author":"Johnson","year":"2015","journal-title":"Blood. 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