DOT1L Mediates Stem Cell Maintenance and Represents a Therapeutic Vulnerability in Cancer

Tumor-initiating cancer stem cells (CSC) pose a challenge in human malignancies as they are largely treatment resistant and can seed local recurrence and metastasis. Epigenetic mechanisms governing cell fate decisions in embryonic and adult stem cells are deregulated in CSCs. This review focuses on the methyltransferase disruptor of telomeric silencing protein 1-like (DOT1L), which methylates histone H3 lysine 79 and is a key epigenetic regulator governing embryonic organogenesis and adult tissue stem cell maintenance. DOT1L is overexpressed in many human malignancies, and dysregulated histone H3 lysine 79 methylation is pathogenic in acute myeloid leukemia and several solid tumors. DOT1L regulates core stem cell genes governing CSC self-renewal, tumorigenesis, and multidrug resistance. Recent work has situated DOT1L as an attractive stem cell target in cancer. These reports showed that DOT1L is overexpressed and its protein activated specifically in malignant stem cells compared with bulk tumor cells, making them vulnerable to DOT1L inhibition in vitro and in vivo. Although early DOT1L inhibitor clinical trials were limited by inadequate drug bioavailability, accumulating preclinical data indicate that DOT1L critically regulates CSC self-renewal and might be more effective when given with other anticancer therapies. The appropriate combinations of DOT1L inhibitors with other agents and the sequence and timing of drug delivery for maximum efficacy warrant further investigation.