Abstract
Disruptor of Telomeric Silencing 1-Like (DOT1L) has emerged as a critical epigenetic regulator in cancer, primarily because of its role as the sole histone methyltransferase responsible for histone H3 at lysine 79 methylation. This modification affects transcriptional activation, DNA repair, and cell cycle progression. Its dysregulation is associated with both hematological and solid tumors. In Mixed-lineage leukemia (MLL)-rearranged leukemia, DOT1L maintains aberrant gene expression patterns at loci such as HOXA and MEIS1, supporting leukemic stem cell survival and driving oncogenesis. In solid tumors, DOT1L influences diverse processes, including epithelial-mesenchymal transition, angiogenesis, and cell cycle regulation, contributing to tumor growth and metastasis. Therapeutic strategies targeting DOT1L using inhibitors, such as EPZ-5676, have shown promise in preclinical and clinical studies, highlighting their potential as versatile targets for precision oncology. This review summarizes the recent findings on DOT1L's involvement in cancer development and its potential as a therapeutic target.