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

Abstract

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.

Leukemogenesis in Acute Lymphoblastic Leukemia through the Lens of Developmental Dynamics of Lymphoid Progenitor Cells: a systematic review

“…Similarly, dysregulated CRLF2 signaling in DS-ALL might indirectly affect Epigenetic Modifiers by modulating downstream signaling pathways involved in their regulation. Perturbations in cytokine receptor signaling cascades could lead to altered expression or activity of Epigenetic Modifiers, resulting in epigenetic alterations that impact LPC differentiation and the leukemic transformation process, thereby contributing to disease pathogenesis [268,269]. JAK2 mutations in DS-ALL can dysregulate Epigenetic Modifiers through the aberrant activation of downstream signaling pathways, particularly the JAK/STAT pathway, which can their expression or activity levels.…”