Histone 3 lysine 9 methylation balance controls transient site-specific DNA amplification and genomic rearrangements of Mixed Lineage Leukemia (MLL)

DNA amplifications and rearrangements are observed in cancer. In infant and adult leukemia as well as therapy-induced leukemia, MLL/KMT2A amplifications and translocations are prevalent. To date, the exact molecular contributor(s) to these alterations are unclear. In this study, we demonstrate that histone H3 K9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus is regulating the amplifications and rearrangements. This balance is controlled by the cross-talk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B loss or chemical suppression increases H3K9me1/2 and reduced CTCF occupancy in KMT2A, and in turn, promotes amplification and rearrangements. Reducing CTCF levels was also sufficient to generate these alterations. Furthermore, Doxorubicin (Dox), which promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. By suppressing G9a or overexpressing KDM3B, the Dox induced MLL/KMT2A alterations are rescued. Therefore, MLL/KMT2A induced amplifications and rearrangements are controlled by distinct epigenetic enzymes that are druggable, which has clinical implications.