Characterization of biological activity and epigenomic remodulation induced by a small-molecule member of hydroxypyrones family in APL blasts

Over the last few decades, hydroxypyrones and their derivatives compounds have been developed and explored due to their versatility, ability in coordinating metal ions and their potential anti-tumor properties. The epigenomic reprogramming potential of maltonis, a novel maltol-derived molecule with promising antiproliferative activity against leukemic cells, has been investigated in the acute promyelocytic leukemia (APL) NB4 cell line. APL is an aggressive subtype of acute myeloid leukemia (AML), and it is characterized by the oncogenic activities of the PML/RARα fusion protein which recruits repressive complexes to the promoter of specific target genes. Indeed, epigenetic perturbations, as alterations of histone H3 lysine 9 trimethylation (H3K9me3), have been frequently found in AMLs and have been associated with leukemogenesis and leukemia progression. The data collected in this work that maltonis treatment induces a profound transcriptomic and epigenomic remodulation, resulting in a global reduction of H3K9me3 signal and modulation of other histone post-translational modifications. Further analysis reveals that maltonis exposure induces substantial changes of genes expression (288 upregulated and 551 downregulated genes) in association with the regulation of the permissive histone H3 marks lysine 4 trimethylation (H3K4me3) and lysine 27 acetylation (H3K27ac) at their gene promoters. Maltonis treatment impacts significatively the interferon alpha and gamma response pathways, upregulating them, while downregulating c-MYC target genes. Notably, the unexpected and substantial antiviral-like response triggered by maltonis may hold the key for understanding its mechanism of action, and it may be speculated a potential connection to the widespread reduction of H3K9me3 mark and the consequent dysregulation of repetitive DNA regions. Collectively, our findings demonstrate the ability of maltonis to reprogram APL cells by epigenetically remodulating their genes expression profile, particularly through the activation of interferon signaling and in the downregulation of c-MYC-related pathways, thus making it an attractive candidate for future clinical applications in anti-leukemic therapy.