The landscape of alterations affecting epigenetic regulators in T-cell acute lymphoblastic leukemia: Roles in leukemogenesis and therapeutic opportunities

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy accounting for 10%-15% of pediatric and 20%-25% of adult ALL cases. Epigenetic irregularities in T-ALL include alterations in both DNA methylation and the post-translational modifications on histones which together play a critical role in the initiation and development of T-ALL. Characterizing the oncogenic mutations that result in these epigenetic changes combined with the reversibility of epigenetic modifications represents an opportunity for the development of epigenetic therapies. Oncogenic mutations and deregulated expression of DNA methyltransferases (DNMTs), Ten-Eleven Translocation dioxygenases (TETs), Histone acetyltransferases (HATs) and members of Polycomb Repressor Complex 2 (PRC2) have all been identified in T-ALL. This review focuses on the current understanding of how these mutations lead to epigenetic changes in T-ALL, their association with disease pathogenesis and the current efforts to exploit these clinically through the development of epigenetic therapies in T-ALL treatment. Epigenetic modifications play a crucial role in orchestrating normal T-cell development. In the context of T-cell acute lymphoblastic leukemia, the discovery of recurrent mutations and dysregulated expression of proteins controling DNA methylation and histone modifications provides promising new avenues for targeted therapeutic interventions.image