Overcoming treatment resistance in acute promyelocytic leukemia and beyond

From the introduction of all-trans retinoic acid (ATRA) to the recent development of arsenic trioxide (ATO) treatment, acute promyelocytic leukemia (APL) characterized by the presence of retinoic acid receptor alpha (RARA) fusion has been transformed from a highly fatal cancer to a highly curable disease. In spite of this unprecedented success, there are still a significant number of high-risk patients who fail to achieve a complete molecular remission or relapse and become resistant to the treatments. Here we discuss the underlying mechanisms and the potential avenue of targeting a critical histone demethylase PHF8 in overcoming the treatment resistance in APL and beyond. As a result of international collaborative research efforts, APL has led the way in demonstrating the promises and defining important principles of successful targeted therapies. At the same time, it also reveals various challenges that targeted therapy will face. Among them is the drug resistance that has taken the central stage. Although the highly specific and effective way of targeting the critical oncogenic events that drive the diseases represents a major advantage over the generic highly toxic chemotherapy, this is a double-edged sword that also makes targeted therapy particularly susceptible to treatment resistance. In APL, ATRA specifically binds to and alters the conformation of oncogenic RARA fusion leading to de-repression of downstream targets by epigenetic reprogramming and subsequent degradation of the fusion proteins, leading to differentiation of APL blasts (Figure 1a). However, a prolonged ATRA treatment can result in drug resistance by inducing and/ or selecting leukemic clones carrying mutations on the ligand binding domain (LBD) of the RARA moiety or aberrant transcription repression complexes that could not be dissociated by ATRA treatment (Figure 1b), which are commonly found in relapse cases. Similar problems also occur in the ATO treatment. PML-RARA fusion accounts for over 98% of APL. Mechanistically, ATO binds directly to PML moiety of the PML-RARA fusion that induces direct cross linking, SUMOylation and subsequent degradation of the fusion protein. In contrast to ATRA, a high dose of ATO triggers apoptosis of APL cells without a significant induction of differentiation (Figure 1c). Although ATO has been successfully used both in combination with ATRA for induction therapy and as a second line treatment for ATRA-resistance, mutations on the PML moiety of the RARA fusion affecting the ATO-induced protein degradation can be found in APL cells after ATO treatment (Figure 1d). Moreover APL patients carrying double mutations affecting …