Small molecule-induced epigenomic reprogramming of APL blasts leading to antiviral-like response and c-MYC downregulation

Abstract

Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML) in which the PML/RARα fusion protein exerts oncogenic activities by recruiting repressive complexes to the promoter of specific target genes. Other epigenetic perturbations, as alterations of histone H3 lysine 9 trimethylation (H3K9me3), have been frequently found in AMLs and are associated with leukemogenesis and leukemia progression. Here, we characterized the epigenomic effects of maltonis, a novel maltol-derived molecule, in APL cells. We demonstrate that maltonis treatments induce a profound remodulation of the histone code, reducing global H3K9me3 signal and modulating other histone post-translational modifications. Transcriptomic and epigenomic analyses revealed that maltonis exposure induces changes of genes expression associated with a genomic redistribution of histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 acetylation (H3K27ac). Upregulation of interferon alpha and gamma response and downregulation of c-MYC target genes, in function of c-MYC reduced expression (monitored in all the hematopoietic neoplasms tested), represent the most significant modulated pathways. These data demonstrate the ability of maltonis to epigenetically reprogram the gene expression profile of APL cells, inducing an intriguing antiviral-like response, concomitantly with the downregulation of c-MYC-related pathways, thus making it an attractive candidate for antileukemic therapy.

Proteomics contributions to epigenetic drug discovery

“…In addition, histone PTMs were profiled in a mouse model of systemic lupus erythematosus [63] and in a human colon cancer cell line [64], to characterize HDAC inhibitors. The epi-proteomics profiling of acute promyelocytic leukemia (APL) cells treated with maltonis, a novel maltol-derived molecule, in APL cells, showed an extensive epigenetic reprogramming of histone PTMs and gene expression profiles, which induce a concomitant antiviral-like response and a downregulation of c-MYC-related pathways, thus making maltonis an interesting candidate for antileukemic therapy [65].…”