DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia

Abstract

MLL -rearrangements generate MLL-fusion proteins that bind DNA and drive leukemogenic gene expression. This gene expression program is dependent on the histone 3 lysine 79 (H3K79) methyltransferase DOT1L, and small molecule DOT1L inhibitors show promise as therapeutics for these leukemias. However, the mechanisms underlying this dependency are unclear. We conducted a genome-scale RNAi screen and found that the histone deacetylase SIRT1 is required for the establishment of a heterochromatin-like state around MLL-fusion target genes after DOT1L inhibition. DOT1L inhibits chromatin localization of a repressive complex composed of SIRT1 and SUV39H1, thereby maintaining an open chromatin state with elevated H3K9 acetylation and minimal H3K9 methylation at MLL-fusion target genes. Furthermore, the combination of SIRT1 activators and DOT1L inhibitors shows enhanced activity against MLL-rearranged leukemia cells. These results indicate that the dynamic interplay between chromatin regulators controlling activation and repression of gene expression could provide novel opportunities for combination therapy.

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…10 Several studies highlight the impact of DOT1L in leukemia, and DOT1L inhibitors show enhanced anti-proliferative activity against MLL-rearranged leukemia cells. 102 Nuclear receptor SET domain-containing (NSD) proteins 1, 2, and 3 Nuclear receptor SET domain-containing (NSD) MTs methylate H3K36. NSDs have been involved in some cases of AML or breast cancers, 70 and NSD2 has been reported as highly overexpressed in GBM.…”

“…102 Protein arginine methyltransferases. Methylation of arginines by protein arginine methyltransferases (PRMT1-9) has been associated with both positive and negative regulation of transcription.…”

Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia

“…DOT1L is an epigenetic modifier that produces mono-, di-, and trimethylated histone H3 lysine 79 (H3K79me1/2/3) (22,23) and maintains a protective chromatin environment against sirtuin 1-dependent (SIRT1-dependent) gene silencing (24). The DOT1L complex is mainly composed of DOT1L, an ENL family protein, and an AF10 family protein, such as AF10 (also known as MLLT10) or AF17 (also known as MLLT6) (13).…”

Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia

“…This leads to loss of H3K9 and H4K16 acetylation and subsequent histone H3 lysine 9 methylation (H3K9me3) via the SUV39 enzymes. This leads to suppression of gene transcription (Chen et al 2015). Therefore, H3K79 methylation may prevent repressive mechanisms from converting chromatin from a state that allows gene expression to a state that does not allow access of the transcriptional machinery.…”