Histone Modifications and Their Targeting in Lymphoid Malignancies

Abstract

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated with somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction, and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in B-cell non-Hodgkin lymphoma. Furthermore, we aim to present in a close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have the greatest potential to improve the prognosis of lymphoma patients.

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

“…Regarding tumour development and progression, several histone modifications have been found. For example, functional dysregulation of histone acetyltransferases has been associated with cancer development, including B-cell [45,46] and T-cell lymphomas [47,48]. In humans, histone modifier gene mutations have been associated with inferior progression-free survival time in patients with T-cell lymphomas [48], and it has been demonstrated that HDAC regulates the expression of BCL6, involved in cell survival and/or differentiation in B-cell lymphoma [49], and HDAC inhibitors have been tried as therapy in humans [50][51][52].…”

Advances in the treatment of relapsed/refractory marginal zone lymphoma

“…These genes play crucial roles in cell proliferation and differentiation, and their mutations can contribute to lymphomagenesis. Additionally, similar patterns of epigenetic modifications, such as DNA methylation and histone modifications, have been observed in both types of lymphoma, underscoring their significant roles in these diseases ( 85 , 86 ). Lastly, there is indeed a convergence in the dysregulation of signaling pathways in MZL and DLBCL.…”

Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development

“…Aberrant EZH2 expression has been associated with various human cancers. For example, the overexpression of EZH2 has been detected in prostate, breast, and other cancers, suggesting that it might serve as a prognostic marker for cancers ( 43 , 81 ). Further, wild-type and mutant EZH2 cooperatively regulate and maintain the hypertrimethylation of H3K27, which inhibits the proliferation of lymphoma cells by abnormally silencing PCR2-target genes ( 47 ).…”