Targeting DNA hypermethylation: Computational modeling of DNA demethylation treatment of acute myeloid leukemia

摘要

In acute myeloid leukemia (AML) DNA hypermethylation of gene promoters is frequently observed and often correlates with a block of differentiation. Treatment of AML patients with DNA methyltransferase inhibitors results in global hypomethylation of genes and, thereby, can lead to a reactivation of the differentiation capability. Unfortunately, after termination of treatment both hypermethylation and differentiation block return in most cases. Here, we apply, for the first time, a computational model of epigenetic regulation of transcription to: i) provide a mechanistic understanding of the DNA (de-) methylation process in AML and; ii) improve DNA demethylation treatment strategies. By in silico simulation, we analyze promoter hypermethylation scenarios referring to DNMT dysfunction, decreased H3K4me3 and increased H3K27me3 modification activity, and accelerated cell proliferation. We quantify differences between these scenarios with respect to gene repression and activation. Moreover, we compare the scenarios regarding their response to DNMT inhibitor treatment alone and in combination with inhibitors of H3K27me3 histone methyltransferases and of H3K4me3 histone demethylases. We find that the different hypermethylation scenarios respond specifically to therapy, suggesting that failure of remission originates in patient-specific deregulation. We observe that inappropriate demethylation therapy can result even in enforced deregulation. As an example, our results suggest that application of high DNMT inhibitor concentration can induce unwanted global gene activation if hypermethylation originates in increased H3K27me3 modification. Our results underline the importance of a personalized therapy requiring knowledge about the patient-specific mechanism of epigenetic deregulation.