Dot1l, short for disruptor of telomeric silencing 1-like protein, is a lysine methyltransferase. It is the sole enzyme responsible for histone three lysine 79 (H3K79) mono -, di -, and tri-methylation. This methylation is involved in multiple cellular processes such as cell cycle progression, DNA damage response, and development. It plays a significant role in normal hematopoiesis, and its aberrant activity is associated with hematopoietic malignancies, especially those with high HOX gene expression [4].

In triple-negative breast cancer (TNBC), inhibition of Dot1l by EPZ-5676 reduces tumor-initiating stem cells and metastasis in xenografts generated from ALDH1+ TNBC cells. Dot1l maintains MYC expression and self-renewal in ALDH1+ cells and governs pathways like oxidative phosphorylation, cMyc targets, DNA damage response, and WNT activation in these cells [1].

In ovarian cancer, the PARP1-Dot1l transcription axis drives acquired resistance to PARP inhibitor. Upregulated Dot1l expression in PARPi-resistant tissues is associated with diminished survival. Combining a Dot1l inhibitor with PARPi shows a synergistic effect [2].

In atherosclerosis, Dot1l inactivation in vascular smooth muscle cells (VSMCs) via an inducible, tissue-specific knockout mouse model significantly reduces disease progression. Dot1l and its induced H3K79me2 mark directly regulate the transcription of Nf-κB-1 and-2 in VSMCs [3].

In summary, Dot1l is crucial for normal hematopoiesis and is involved in multiple disease processes. Gene knockout models in different tissues have revealed its role in cancer metastasis, drug resistance, and atherosclerosis development. These findings highlight Dot1l as a potential therapeutic target for various diseases.