Review Chronicles Advancing Insights Into Epigenetic Alterations in Chronic Lymphocytic Leukemia

Recent advances in understanding the epigenetic mechanisms and targeted therapies for chronic lymphocytic leukemia (CLL) have led to better and earlier identification of the exact function of epigenetic alterations, solidifying targeting epigenetics as one direction for the future treatment of CLL, according to a review published in Clinical and Experimental Medicine.

CLL cells in blood flow | Image Credit: © Laszlo - stock.adobe.com

Epigenetic modifications have been found to play significant roles in the occurrence and development of leukemia while achieving positive clinical effects. Due to this, they have been considered a promising target for treating different types of leukemia, the investigators wrote.

Importantly, epigenetic research has made strong progress in promoting the comprehension of the pathogenesis of CLL. The present review summarizes advances in CLL epigenetics, such as DNA methylation, histone modification, RNA methylation, and others.

Beginning with DNA methylation, the investigators noted that it has been found to be associated with an increasing number of diseases by participating in many cellular processes. Additionally, they note that an assessment of global DNA methylation/demethylation levels can improve outcome prediction in patients with CLL.

Mutations of splicing factor 3b subunit 1 (SF3B1) have been associated with adverse prognosis, the investigators wrote. A study exploring the connection between methylome changes and SF3B1 mutation found that methylation levels in 67 genomic regions in patients with CLL were localized declined.

Secreted frizzled-related protein 4 (SFRP4) plays a negative role in the Wnt signaling pathway, which is essential for the development of normal B cells and has been shown to control the apoptotic process. A study of 5 SFRP family members found that SFRP1 was hypermethylated and downregulated in CLL samples, which indicates that this is a key step in the development of leukemia, the investigators wrote.

Histone methyltransferase aberrations have been found in human malignancies, one of them being the repeated deletion and/or inactivating mutations of SETD2, which is a cancer suppressor gene. The investigators described SETD2 abnormity as a frequent and early loss-of-function event that is associated with aggressive disease in the pathology of CLL.

Moving on to RNA methylation, the investigators wrote that is of great significance in regulating gene expression. Demethylases, which include fat mass and obesity-associated protein (FTO) and alkylation repair homolog 5 (ALKBH5), mediate the procedures of RNA demethylation. These demethylases locate to nuclear speckles, which participate in the process of methylation, the investigators wrote.

Evidence was found that FTO contributes to the development and progress of AML, and that FTO expression was upregulated in CLL patients and related to a poor prognosis. Additionally, they have been seen to accelerate the survival of CLL cells. The investigators discussed how a novel inhibitor that selectively targets FTO has therapeutic potential in eliminating cell survival and beginning cell cycle arrest.

Chromatin remodelers, consisting of 4 families of genetic alterations, are involved in many pathological processes in CLL, the investigators found. Furthermore, some mutations involving chromatin remodeling have been observed to affect ARID1A and CHD2 genes in hematological malignancies, including CLL, indicating its importance in the pathology of the disease.

Overall, the investigators emphasized the importance of better and earlier identification of the exact function of epigenetic alterations, encompassing DNA methylation, RNA methylation, noncoding RNAs and other sectors, noting that they can provide new insights into treating and curing CLL.

“Although there are few mature epigenetic regulators, targeting epigenetics is still one of the directions for the future treatment of CLL,” the investigators concluded.

Reference

Zhang X, Wang H, Zhang Y, Wang X. Advances in epigenetic alterations of chronic lymphocytic leukemia: from pathogenesis to treatment. Clin Exp Med. 2024 Mar 16;24(1):54. doi:10.1007/s10238-023-01268-x