Arsenic induced epigenetic changes and relevance to treatment of acute promyelocytic leukemia and beyond.

Epigenetic alterations regulate gene expression without changes in the DNA sequence. It is well-demonstrated that aberrant epigenetic changes contribute to the leukemogenesis of acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) is one of the most common drugs used in the frontline treatment of APL that act through targeting and destabilizing the PML/RARα oncofusion protein. ATO together with all-trans retinoic acid (ATRA) lead to durable remission of more than 90% non-high-risk APL patients, turning APL treatment into a paradigm of oncoprotein targeted cure. Although relapse and drug resistance in APL are yet to be resolved in the clinic, epigenetic machineries might hold the key to address this issue. Further, ATO also showed promising anticancer activities against a variety of malignancies, but its application is particularly restricted due to limited understanding of the mechanism. Thus, a thorough understanding of epigenetic mechanism behind anti-leukemic effects of ATO would benefit the development of ATO-based anticancer strategy. Role of ATRA on APL associated epigenetic alterations has been extensively studied and reviewed. Recently, accumulating evidence suggest that ATO also induces some epigenetic changes that might favor APL eradication. In this article, we comprehensively discuss arsenic induced epigenetic changes and its relevance in APL treatment and beyond, so as to provide novel insights into overcoming arsenic resistance in APL and promote application of this drug to other malignancies.