PHF8 Mediates ATRA Sensitivity in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia distinguished by retinoic receptor alpha (RARA) gene fusions. Treatment with all-trans retinoic acid (ATRA) leads to complete remissions in many patients, but the underlying mechanisms of ATRA response and the reasons why some patients relapse and become ATRA insensitive remain poorly understood. Given evidence indicating that ATRA derepresses RARα fusion targets through recruitment of coactivator complexes, Arteaga and colleagues screened for ATRA-induced interactions between PML–RARα, the most common RARα fusion, and histone lysine demethylases, which have been linked previously to transcriptional activation and retinoic acid signaling. Upon ATRA treatment, a specific interaction was only found between PML–RARα and PHD finger protein 8 (PHF8), and PHF8 was recruited to PML–RARα target promoters, where it was associated with a reduction in repressive methylation marks and increased transcription. Notably, PHF8 expression was much lower in an ATRA-resistant APL cell line than in its ATRA-sensitive parental cell line, suggesting that PHF8 regulates ATRA sensitivity in APL cells. Indeed, forced expression of PHF8 restored ATRA sensitivity in resistant APL cells both in vitro and in vivo, and PHF8 knockdown in ATRA-sensitive cells conferred resistance. Phosphorylation of PHF8 was also critical for its ability to reactivate RARα fusion targets upon ATRA treatment, and inhibition of PHF8 dephosphorylation with a phosphatase inhibitor also sensitized resistant APL cells to ATRA treatment. Although it remains to be shown whether PHF8 expression is decreased in ATRA-resistant patients, these findings provide insight into the molecular mechanisms of ATRA response and raise the possibility that modulation of PHF8 activity could overcome ATRA resistance in patients with relapsed APL.

Arteaga MF, Mikesch JH, Qiu J, Christensen J, Helin K, Kogan SC, et al. The histone deacetylase PHF8 governs retinoic acid response in acute promyelocytic leukemia. Cancer Cell 2013;23:376–89.