Arteaga, Maria Francisca4; Mikesch, Jan-Henrik4; Qiu, Jihui4; Christensen, Jesper Aagaard5; Helin, Kristian5; Kogan, Scott C4; Dong, Shuo4; So, Chi Wai Eric4
1 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet2 BRIC Administration, BRIC, Københavns Universitet3 The Danish Stem Cell Center, Faculty of Health and Medical Sciences, Københavns Universitet4 unknown5 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet
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.