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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 RAR? 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.

SUBMITTER: Arteaga MF

PROVIDER: S-EPMC6812572 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia.

Arteaga Maria Francisca MF Mikesch Jan-Henrik JH Qiu Jihui J Christensen Jesper J Helin Kristian K Kogan Scott C SC Dong Shuo S So Chi Wai Eric CW

Cancer cell 20130301 3

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 res ...[more]

PMID: 23518351

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