J. Przybilla, L.Hopp, M. Luebbert, M. Scholz, J. Galle, M. Loeffler
Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University
Objectives:
In Acute Myeloid Leukemia (AML) the number of associated gene mutations is low but some of them are related to epigenetic modifiers. One frequently observed epigenetic pathology is DNA hypermethylation of gene promoters which often results in modifications in gene-expression and a blockade of differentiation. Treatment of AML patients with DNA methyltransferase (DNMT) inhibitors as Azacitidine and Decitabine results in global hypomethylation of genes and thereby, can lead to a reactivation of the natural differentiation capability of leukemia cells. However, due to the reversibility of epigenetic changes, hypermethylation and differentiation blockade often return after stopping the treatment.
We developed a single cell and multiscale computational model of epigenetic regulation of transcription in order to provide a mechanistic understanding of the DNA (de-) methylation process in AML and to construct a predictive model of DNA demethylation treatment strategies. Our general objective is to develop new hypothesis for epigenetic therapies by in silico simulations of our mechanistic model.
Methods:
Our computational model considers a cell population of individual cells. The cells do not interact. Each cell contains the same random genome that generates an artificial transcription factor network which is regulated by itself. Activating and repressing transcription factors are equal distributed. The main focus in our modeling is the additional layer of transcriptional regulation by epigenetic regulatory factors. These factors are DNA methylation of promoters, the activating histone modification H3K4me3 and the repressing histone modification H3K27me3. In our model, both histone modifications are directly incorporated in transcriptional regulation. In contrast, DNA methylation is regulated by binding of histone modification enzymes. By computational simulations, 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.
Results:
We found that the different hypermethylation scenarios respond specifically to therapy, suggesting that a failure of remission originate in patient specific deregulation [1]. We also observed that inappropriate demethylation therapy could also be detrimental in the sense that it could result in increased deregulation. As an example, our results suggest that application of high DNMT inhibitor concentrations can induce unwanted global gene activation if hypermethylation originates in increased H3K27me3 modification.
Conclusions:
Our modelling results underline the importance of a personalized therapy requiring knowledge about the patient-specific mechanism of epigenetic deregulation. From our model simulations we conclude that DNA demethylation therapy allows the reestablishing of a natural gene expression state of leukemia cells by the regeneration of the histone modification states.
References:
[1] Przybilla J., Hopp L., Luebbert M., Loeffler M., Galle J.,Targeting DNA hypermethylation: Computational modeling of DNA demethylation treatment of acute myeloid leukemia. Epigenetics. 2017;12(10):886-896. doi: 10.1080/15592294.2017.1361090.
Reference: PAGE 27 (2018) Abstr 8550 [www.page-meeting.org/?abstract=8550]
Poster: Drug/Disease Modelling - Other Topics