Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies

Abstract

Hematologic malignancies are one of the most common cancers, and the incidence has been rising in recent decades. The clinical and molecular features of hematologic malignancies are highly heterogenous, and some hematologic malignancies are incurable, challenging the treatment, and prognosis of the patients. However, hematopoiesis and oncogenesis of hematologic malignancies are profoundly affected by epigenetic regulation. Studies have found that methylation-related mutations, abnormal methylation profiles of DNA, and abnormal histone deacetylase expression are recurrent in leukemia and lymphoma. Furthermore, the hypomethylating agents and histone deacetylase inhibitors are effective to treat acute myeloid leukemia and T-cell lymphomas, indicating that epigenetic regulation is indispensable to hematologic oncogenesis. Epigenetic regulation mainly includes DNA modifications, histone modifications, and noncoding RNA-mediated targeting, and regulates various DNA-based processes. This review presents the role of writers, readers, and erasers of DNA methylation and histone methylation, and acetylation in hematologic malignancies. In addition, this review provides the influence of microRNAs and long noncoding RNAs on hematologic malignancies. Furthermore, the implication of epigenetic regulation in targeted treatment is discussed. This review comprehensively presents the change and function of each epigenetic regulator in normal and oncogenic hematopoiesis and provides innovative epigenetic-targeted treatment in clinical practice.

Small-molecule probes from bench to bedside: advancing molecular analysis of drug–target interactions toward precision medicine

“…HDACs regulate histone acetylation and act as transcriptional repressors, and their dysregulation is associated with hematological malignancies and lymphomas. 287 The study utilized blood-TPP to profile the targets of panobinostat, confirming its engagement with known HDACs in human whole blood and identifying an off-target, the zinc finger protein ZNF512. Furthermore, blood-CETSA was used to quantify and compare the dose-dependent engagement of HDAC2 by different HDAC inhibitors, including belinostat and romideps.…”

Long non‐coding RNA as a novel biomarker and therapeutic target in aggressive B‐cell non‐Hodgkin lymphoma: A systematic review

“…Recently, many studies have demonstrated that lncRNAs are involved in different malignancies, including lymphomas. In haematologic malignancies, lncRNAs may affect cell proliferation, invasion and resistance to treatment through different pathways 8 …”

“…In haematologic malignancies, lncRNAs may affect cell proliferation, invasion and resistance to treatment through different pathways. 8 Furthermore, studies have shown changes in lncRNA expression in different stages of the maturation of lymphocytes. 9 Understanding the lncRNA mechanism of action provides more information about lymphoma's pathogenesis.…”

Hematopoiesis: a BETter understanding

“…Its absence severely impacts immune system function and leads to developmental defects in HSCs and impaired macrophage proliferation (Dey et al, 2019). In this issue, Yang et al (2023) extensively investigate various progenitor cell populations and their lineage commitment to myeloid cells in the absence of BRD4. The conditional deletion of BRD4 in the hematopoietic system of 6-8-week-old mice results in lethality and a substant increase in HPCs that possess, however, restricted colony-forming capacity and selfrenewal activity.…”

“…In apparent contrast, in macrophages in the absence of BRD4, ligand-induced NF-jB binding is not reduced; instead, it increases, leading to significant inflammatory responses in BRD4 KO macrophages (Dey et al, 2019). However, the exact mechanism responsible for this unexpected finding remained unclear until the work of Yang et al (2023), which sheds light on this contrasting observation.…”