DOT1L, also known as disruptor of telomeric silencing 1-like protein, is the sole methyltransferase responsible for histone three lysine 79 (H3K79) mono -, di -, and tri-methylation. It is involved in multiple cellular processes such as cell cycle progression, DNA damage response, and development. In normal hematopoiesis, DOT1L is essential as its knockout leads to impairment in blood lineage formation. Aberrant DOT1L activity is implicated in hematopoietic malignancies, especially those with high HOX gene expression [4].

In triple-negative breast cancer (TNBC), DOT1L is a key cancer stem cell (CSC) regulator. Inhibiting DOT1L with EPZ-5676 reduces tumorspheres and ALDH1 + cells in vitro, and decreases tumor-initiating stem cells and metastasis in xenografts generated from ALDH1 + cells in vivo [1]. In ovarian cancer, the PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor. Targeted inhibition of DOT1L may enhance PARPi treatment outcomes [2]. In atherosclerosis, Dot1l inactivation in vascular smooth muscle cells (VSMCs) via an inducible, tissue-specific knock-out mouse model significantly reduces disease progression. DOT1L and its induced H3K79me2 mark directly regulate the transcription of Nf-κB-1 and-2, which in turn induce the expression of cytokines involved in atherosclerosis development [3].

In summary, DOT1L plays crucial roles in various biological processes and diseases. Gene knockout models, especially in mouse studies, have revealed its functions in cancer, atherosclerosis, and normal development. Understanding DOT1L's functions provides potential therapeutic targets for treating related diseases.

References:

1. Kurani, Hetakshi, Razavipour, Seyedeh Fatemeh, Harikumar, Kuzhuvelil B, Wahlestedt, Claes, Slingerland, Joyce. . DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer. In Clinical cancer research : an official journal of the American Association for Cancer Research, 28, 1948-1965. doi:10.1158/1078-0432.CCR-21-1299. https://pubmed.ncbi.nlm.nih.gov/35135840/

2. Liu, Chaohua, Li, Jiana, Xu, Fei, Wu, Xiaohua, Chen, Xiaojun. 2024. PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer. In Molecular cancer, 23, 111. doi:10.1186/s12943-024-02025-8. https://pubmed.ncbi.nlm.nih.gov/38778348/

3. Farina, Floriana Maria, Serio, Simone, Hall, Ignacio Fernando, Quintavalle, Manuela, Elia, Leonardo. . The epigenetic enzyme DOT1L orchestrates vascular smooth muscle cell-monocyte crosstalk and protects against atherosclerosis via the NF-κB pathway. In European heart journal, 43, 4562-4576. doi:10.1093/eurheartj/ehac097. https://pubmed.ncbi.nlm.nih.gov/35292818/

4. Arnold, Olivia, Barbosa, Karina, Deshpande, Aniruddha J, Zhu, Nan. 2022. The Role of DOT1L in Normal and Malignant Hematopoiesis. In Frontiers in cell and developmental biology, 10, 917125. doi:10.3389/fcell.2022.917125. https://pubmed.ncbi.nlm.nih.gov/35712672/