Cellular transformation by oncogenes involves disturbance of multiple cellular systems. Epigenetic changes occur frequently in transformed cells and might serve several functions. On the one hand side, epigenetic alterations such as altered promoter DNA methylation could contribute to the malignant phenotype by affecting gene expression levels. On an even more global level, epigenetic marks and especially DNA methylation could corroborate the malignant phenotype by disrupting the three dimensional chromosomal architecture. A variety of genetic mutations can initiate acute myeloid leukemia [1]. Several mutations associate with specific DNA methylation patterns [2]. The mechanisms how such aberrant methylation patterns are established remain enigmatic. PML-RARα is an oncogene that induces acute promyelocytic leukemia (APL). Recently, we dissected the methylome of APL at base pair resolution [3]. Genome-wide hypermethylation in CpG rich regions was a representative characteristic of APL. Intriguingly, PML-RARα binding-sites remained non-methylated and appeared protected from the actual hypermethylation phenotype in APL. In contrast to this protection from DNA methylation, PML-RARα target-genes are silenced via recruitment of histone deacetylases (HDACs) to PML-RARα binding-sites [4, 5]. Surprisingly, the actual binding of PML-RARα takes place at accessible chromatin [6], which together with our data underscores that heterochromatin formation at PML-RARα targeted genes is not required for APL pathogenesis. Interestingly, the repressive action of PML-RARα can be efficiently switched off upon ATRA treatment, which is directly translated to increased histone acetylation and gene expression without a change in DNA methylation [5]. While histone deacetylation is directly linked to HDAC recruitment by PML-RARα it remains unclear how specific DNA methylation patterns are being established. In addition, the fundamental question emerges, whether DNA methylation aberrations contribute to leukemia or remain downstream events in a PML-RARα transformed cell.

Recent whole genome sequencing data from human APL patients and a mouse APL model system consolidated that PML-RARα is the initiating event in APL, but underscored that cooperating mutations (ie mainly FLT3) are needed to induce the disease [1]. In this view, PML-RARα provides a competitive growth advantage for t (15; 17)-positive cells and increases the probability