title: The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia.
abstract: While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RARα fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance.
authors.affiliation: Leukaemia and Stem Cell Biology Group, Department of Haematological Medicine, King's College London, Denmark Hill, London SE5 9NU, UK.
authors.forename: Maria Francisca
authors.initials: MF
authors.lastname: Arteaga
authors.forename: Jan-Henrik
authors.initials: JH
authors.lastname: Mikesch
authors.forename: Jihui
authors.initials: J
authors.lastname: Qiu
authors.forename: Jesper
authors.initials: J
authors.lastname: Christensen
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Shuo
authors.initials: S
authors.lastname: Dong
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D006657:Histones; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D034741:RNA, Small Interfering; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D019319:Okadaic Acid; D014212:Tretinoin; D056466:Histone Demethylases; C553256:PHF8 protein, mouse