The Histone Demethylase PHF8 Governs Retinoic Acid Response in Acute Promyelocytic Leukemia

SummaryWhile 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.

Graphical AbstractFigure optionsDownload high-quality image (75 K)Download as PowerPoint slideHighlights
► Histone demethylase PHF8 is recruited by PML-RARα upon ATRA treatment in APL
► Enzymatic activity and serine phosphorylation of PHF8 are required for ATRA response
► Activation of PHF8 confers ATRA sensitivity to resistant APL cells in vivo
► Pharmacological inhibition of PHF8 dephosphorylation sensitizes ATRA-resistant cells